- Email: [email protected]
Infectious Adverse Events Following the Placement of a Penile Prosthesis: A Systematic Review
REVIEW
Infectious Adverse Events Following the Placement of a Penile Prosthesis: A Systematic Review Joseph Mahon, MD,1 Ryan Dornbier, MD,1 Grace Wegrzyn, BS,2 Martha M. Faraday, PhD,3 Hossein Sadeghi-Nejad, MD,4 Lawrence Hakim, MD,5 and Kevin T. McVary, MD-FACS1
ABSTRACT
Introduction: Infection remains a prominent concern following penile implantation. Recognition of the risk factors for infection may help to guide surgeons toward reducing the risk of prosthetic contamination. Aim: To gain a further understanding of infectious adverse events following penile prosthesis, we performed a systematic literature review. Methods: As part of the 2018 American Urological Association Erectile Dysfunction Clinical Guidelines and with the support of the American Urological Association, we performed a comprehensive review of the PubMed, Embase, and Cochrane databases to search for eligible articles published between January 1, 1965, and July 20, 2016, to identify articles reporting infectious adverse events following prosthesis placement. Main Outcome Measure: The main outcome measure was infectious adverse events following penile prosthesis placement. Results: Ninety-one articles reporting infectious adverse events representing 97 study arms were identified. Prosthetic infection rates ranged from 0% to 24.6% across all series. Inflatable penile prostheses displayed a wider range (0e24.6%) than malleable devices (0e9.1%); the most frequently reported infection rate for inflatable devices was 5% or less. With the advent of device coatings and improved surgical techniques, infectious adverse events have decreased. Infections among diabetic patients also decreased throughout the reviewed body of literature, with the most recent series reporting rates consistent with those of non-diabetic patients. Furthermore, no glycosylated hemoglobin cutoff was found to infer increased or decreased risk of prosthesis infection. Conclusion: Overall penile prosthetic infectious adverse events have decreased as surgical techniques have improved and the use of antimicrobial coating has gained in popularity. These advances have demonstrated significant benefits for all patients, particularly diabetic patients who experience infection rates similar to those of non-diabetic patients in recent reports. Further technological advancements for the prevention of biofilm formation is warranted. Mahon J, Dornbier R, Wegrzyn G, et al. Infectious Adverse Events Following the Placement of a Penile Prosthesis: A Systematic Review. Sex Med Rev 2019;XX:XXXeXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile Dysfunction; Penile Prosthesis; Infectious Adverse Event
Received May 22, 2019. Accepted July 11, 2019. 1
Center for Male Health, Department of Urology, Loyola University Stritch School of Medicine, Maywood, IL;
2
Loyola University Stritch School of Medicine, Maywood, IL;
3
Four Oaks Consulting, Inc, Berryville, VA;
4
Department of Urology, Hackensack University Medical Center, Hackensack, NJ, and Division of Urology, Rutgers New Jersey Medical School, Newark, NJ;
5
Department of Urology, Cleveland Clinic Florida, Weston, FL
Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.sxmr.2019.07.005
Sex Med Rev 2019;-:1e7
INTRODUCTION Some degree of erectile dysfunction (ED) is reported by 52% of male patients between 40 and 70 years of age, with a projected worldwide prevalence of 322 million men by the year 2025.1,2 Etiologies of ED encompass both organic and psychogenic causes, including advanced age, obesity, smoking, cardiovascular disease, diabetes mellitus, dyslipidemia, depression, and benign prostatic hyperplasia, which are wellknown risk factors and comorbid conditions.3,4 Regardless of cause, ED has a significant impact on sexual and overall quality of life.5e7 1
2
Over the last 50 years, treatment modalities for ED have expanded significantly. Pharmacologic therapies with phosphodiesterase-5 inhibitors, intracavernosal injections, and intraurethral alprostadil allow for non-surgical management; however, at least 30% of patients will experience failure or significant side effects with phosphodiesterase-5 inhibitors.8 Additionally, intracavernosal injections are associated with high discontinuation rates related to either patient dissatisfaction or cost.9,10 Alternatively, penile prosthesis placement represents the most definitive ED therapy given its ondemand functionality and high rates of satisfaction among patients and their partners.11,12 These quality of life improvements notwithstanding, penile prosthesis surgery is associated with complications. An infectious adverse event following penile prosthesis is a devastating complication and remains of paramount concern for the prosthetic surgeon. In most instances, a clinical device infection requires complete removal of the prosthesis with or without salvage reimplantation.13,14 Moreover, the subsequent corporal fibrosis makes device reimplantation more difficult and susceptible to adverse events, in addition to being associated with decreased patient satisfaction.15,16 Proposed risk factors for prosthesis infection include smoking status, diabetes, concurrent urinary tract infection or skin infection, prolonged operative time, revision surgery, and spinal cord injury.17,18 There has been significant attention given to preventing prosthesis infection with risk factor optimization, device modifications, and surgical techniques. To gain further understanding of current factors influencing infectious adverse events after penile prosthesis placement, we performed a systematic literature review.
METHODS This review was performed in conjunction with the 2018 American Urological Association (AUA) Erectile Dysfunction Guidelines,19 with support of the AUA Clinical Guidelines Office (Linthicum, MD). A systematic literature review was performed using the PubMed, Embase, and Cochrane databases to search for articles published between January 1, 1965, and July 20, 2016, using select key words to identify articles reporting on the treatment of ED with penile prostheses and outcomes data related to infectious adverse events. Titles and abstracts were reviewed for relevance, and preliminary exclusions were made. The relevant articles were retrieved in full-text form for a more detailed analysis, and additional exclusions were made after the full-text review. Articles reporting on preclinical data, animal models, devices of historical significance, devices no longer available, and reports no longer relevant to clinical practice were excluded. Studies were also excluded if outcomes data and adverse events were not reported, if infectious outcomes were not reported, if the reports duplicated the same patient populations, or if there was a small sample size (10 patients). All studies selected for analysis were assessed for quality. Systemic reviews were assessed using A Measurement Tool to Assess Systematic Reviews.20 Randomized controlled trials (RCTs) and controlled clinical trials were analyzed using the Cochrane risk-of-
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bias tool.21 Case-control studies and comparative observational studies were rated using the Newcastle-Ottawa Quality Assessment Scale.22 Due to their inherent variability, single-arm cohort studies were not assessed for quality. In addition to quality measures, each selected study was assigned a body of evidence strength in accordance with standard AUA guideline categorization: Grade A (well-conducted and highly generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data).23
RESULTS Database searches returned 267 articles, with 91 articles meeting inclusion criteria for full text review. All of the studies were observational in design, resulting in a body of evidence strength Grade C. Infectious outcomes were reported in 97 total study arms involving an inflatable penile prosthesis (IPP) or a malleable penile prosthesis (MPP), a variety of prosthesis subtypes, and patient populations (Table 1). In studies of the general ED population, infectious adverse events ranged from 0% to 24.6%.
IPP vs. MPP IPPs had a wider range of infectious adverse events (0e24.6%) than did MPPs (0e9.1%), and infectious adverse events for mixed IPP and MPP cohorts ranged from 0.5% to 13.7%. Of the 68 study arms that reported infection rates for IPPs, 7 arms (10.3%) reported rates of 0%, 26 arms (38.2%) reported rates of <2%, and 52 arms (76.5%) reported rates of <5%. Among 12 MPP cohorts, 4 study arms (33.3%) reported rates of <2%, and 6 study arms (50%) reported rates of <5%. In the remaining 11 cohorts reporting on mixed IPP and MPP cohorts, 2 (18.2%) reported rates of <2%, and 6 (54.5%) reported rates of <5%. Multiple studies have reported on the direct comparison of IPP models and MPP models, most in small case series. Bozkurt et al24 reported on men with the AMS 700CX, Ambicor, or Ultrex (n ¼ 118) (Boston Scientific; Marlborough, MA) or the AMS 600-650 (Boston Scientific) or Mentor Acu-Form (Mentor Worldwide; Irvine, CA) (n ¼ 139); follow-up durations were 34 and 52 months, respectively. The infection rate was higher in the inflatable group (4.2%) compared to the malleable group (1.44%), but this difference was not statistically significant. Additional information can be garnered from a comparison between the AMS 600 and AMS 700CX devices reported by Earle and colleagues.25 In their study, 57 men had the AMS 600 implanted, and 23 men had the AMS 700CX implanted; followup duration was not reported. Infection rates were 3.5% for the Sex Med Rev 2019;-:1e7
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Infectious Adverse Events Following Placement of Penile Prosthesis
Table 1. Infection rates by patient category, prosthesis type, and prosthesis subtype
Patient category
Prosthesis type
Prosthesis subtype
Study arms (n)
General population
Inflatable
AMS 700 Series AMS 700CX, Ambicor, or Ultrex AMS Ambicor or Coloplast Excel Mentor Alpha 1 and NB Coloplast Titan Other or multiple or unspecified inflatables Unspecified AMS Spectra malleable AMS 600-650 malleable AMS 600-650 or Mentor Acu-Form Other or multiple or unspecified malleable Mixed inflatable and malleable models AMS 700 series or Coloplast Titan AMS 700 series or Coloplast Titan Other or multiple or unspecified inflatables Mixed inflatable and malleable models AMS 600-650 malleable
27 1 1 11 8 19 1 1 6 1 4 11 1 1 2 1 1
Malleable
Diabetes Post-prostatectomy
Inflatable or malleable Inflatable Inflatable
Spinal cord injury
Inflatable or malleable Malleable
malleable model and 0% for the inflatable device. Altunkol et al26 reported on men with the AMS 700CX (n ¼ 16) or the AMS Spectra malleable (n ¼ 18); follow-up durations were 24.1 and 29.4 months, respectively. The infection rates were comparable in the inflatable group (6.3%) and the malleable group (5.6%). No study directly comparing IPP and MPP infectious adverse events was statistically significant. This suggests that the rates of infection for IPPs and MPPs are similar, with no increased risk of infection with either prosthesis type.
Device Coating The introduction of infection-retardant coating has drastically reduced the infection rate across device models. In a retrospective review comparing the AMS 700 with (n ¼ 58) and without (n ¼ 94) rifampin/minocycline (InhibiZone) impregnation, infection rates for the InhibiZone devices were significantly less (0%) compared to those for the non-InhibiZone devices (3.2%).27 Using patient information forms to compare AMS 700 series prostheses with InhibiZone (n ¼ 35,737) to those without InhibiZone (n ¼ 3,268) in terms of the need for revision as a result of infection (infection rates that did not require revision were not reported), Carson et al28 showed that the InhibiZone device was significantly less likely to require revision for infection (1.1%) compared to the same device without InhibiZone (2.5%). A hydrophilic coating on Coloplast devices (Coloplast Corp; Minneapolis, MN) also limits infection rates. Using patient information forms to compare the Coloplast Titan model with a hydrophilic coating (n ¼ 29,360) to the same model without a hydrophilic coating (n ¼ 7,031), Serefoglu and colleagues29 showed that the infection rate was significantly lower (1.4%) with the hydrophilic coating compared to no coating (4.6%). Eid and colleagues30 examined infection rates among men implanted with either the Sex Med Rev 2019;-:1e7
Infection rate (%) Minimum
Maximum
Mean
0.00 4.20 4.80 1.20 0.00 .10 5.60 5.60 1.40 1.44 0.00 .50 3.60 0.00 .81 3.30 8.30
11.80 4.20 4.80 24.60 9.00 15.90 5.60 5.60 9.10 1.44 8.90 13.70 3.60 0.00 1.10 3.30 8.30
3.42 4.20 4.80 4.57 2.86 4.88 5.60 5.60 4.93 1.44 4.08 5.92 3.60 0.00 0.96 3.30 8.30
Coloplast Titan model or the AMS 700 series (results not separated by model) that either had no infection-inhibiting coating (n ¼ 132) or had an infection-inhibiting coating (n ¼ 704). Infection rates for the non-coated group were 5.3% compared to 1.99% for the coated models. Notably, these studies are limited by their retrospective nature and utilization of historical controls for comparison. Only limited data directly compare the types of antibiotic coatings or solutions applied to devices. Dhabuwala and colleagues31 compared infection rates among the Coloplast Titan model coated with rifampin/gentamicin (n ¼ 81), the same model coated with vancomycin/gentamicin (n ¼ 181), and AMS 700 series models coated with InhibiZone (n ¼ 77). Infection rates were 0% for the rifampin/gentamicin group, 4.4% for the vancomycin/gentamicin group, and 1.3% for the AMS series with InhibiZone. The combined group of the Coloplast Titan coated with rifampin/gentamicin and the AMS series with InhibiZone saw an infection rate of 0.63%, suggesting a decreased infection rate with rifampin inclusion. Additional conclusions regarding the type of antibiotic coating cannot be reached, other than the direct comparisons made in this study. Further information regarding antibiotic solutions is limited, as many studies were preclinical in nature.
Surgical Technique and Revision Surgery The use of novel surgical techniques for infection reduction has been reported. The “no touch” technique describe by Eid et al30 in 2012 demonstrated improved infection rates among men implanted with a device that had an infection-retardant coating. In the “no touch” technique, the initial penoscrotal incision is made with dissection carried down to the level of Buck’s fascia. At this time, the procedure is halted, and all
4
surgical instruments used are considered contaminated and discarded. An additional plastic drape is placed over the retractor and surgical field, incised, and secured to the cut skin edge. The prosthesis implantation then proceeds through the cut drape. The group reported a reduction in infection rate from 1.99% without the technique to 0.46% with the technique; however, this study was not randomized and utilized historical controls for comparison to the “no touch” technique. Moreover, the results of this study have not been validated by additional surgeons. With respect to surgical site approach, no apparent difference in infection rates has been found. Garber and Marcus32 compared infection rates based on surgical approach among 360 men undergoing a first IPP placement. Infection rates were 2.9% for 139 infrapubic approaches and 0.9% for 221 scrotal approach cases; however, the difference was not statistically significant. Further information regarding surgical technique was garnered from Moncada et al.33 In their report, 100 patients were implanted with AMS 700 series devices with or without corporeal dilation, and the infection rate was identical at 2% between the 2 groups at 9-month follow-up. We noted that infectious adverse events increase in the setting of revision surgery. Jarow18 initially reported on infection rates for initial implantations among 114 men and for revision implants among 30 men. The infection rate was significantly higher for revision procedures (13.3%) compared to initial procedures (1.8%). Further information was reported by Abouassaly et al34 for 55 men undergoing explant of an inflatable prosthesis for mechanical failure and reimplant with an InhibiZone-coated model. At median follow-up of 32 months, 1 patient (1.8%) had developed an infection. Additional information can be gleaned from subgroup analyses from studies not directly comparing or evaluating revision surgeries. Using a variety of prosthesis models, Lotan and colleagues35 reported infection rates of 9.9% and 18.8% for primary and secondary implantation, respectively. According to Wilson and colleagues,36 infection rates among patients receiving IPPs with the InhibiZone coating were 0.33% for virgin implants (n ¼ 306) and 5.0% for revision implants (n ¼ 161).
Patient Population (Diabetics, Post-Prostatectomy, Spinal Cord Injury) Limited data are available offering direct comparison of specific patient populations. A single study reported on the use of the AMS 600 malleable prosthesis in patients with spinal cord injury. Of the 48 men followed for an average of 139 months, 4 (8.3%) developed infection. Two of the infectious events were managed conservatively, but the other 2 required device explantation.37 This study represents a small sample size; thus, specific conclusions regarding risk of penile prosthesis infection for men with spinal cord injury cannot be made. An area of regular concern for the prosthetic surgeon remains the influence of diabetes mellitus on infection rate. Few studies meeting the inclusion criteria specifically identified patients with
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diabetes as a comparison cohort. Several studies reporting on patients with diabetes were excluded because of a focus on only historically relevant devices. Wilson and colleagues38 followed 389 men (including 114 diabetic men) for 2 years after inflatable prosthesis implantation to evaluate whether elevated glycosylated hemoglobin (HgbA1c) was a risk factor for infection. Infections developed in 8.7% of diabetic men and 4.0% of non-diabetic men, a difference that reached borderline statistical significance (P ¼ .06); however, HgbA1c levels were not significant predictors of infection for diabetic or non-diabetic men. In their investigation of surgical approaches, Garber and Marcus32 found infection rates of 2.8% among diabetic patients and 0.9% among non-diabetic patients; this difference also was not statistically significant. In a large case series of 2,347 IPPs reported by Eid et al30 (discussed earlier with regard to the “no touch” technique for antibiotic-coated devices), 41% of the population had a diagnosis of diabetes. Infection rates were 0.6% for the diabetic population and 1.5% for the non-diabetic population. Christodoulidou and Pearce39 conducted a systematic review analyzing case series using historical and current devices. Most reports of higher infection rates were among historical devices, but large modern case series using devices with antibiotic coatings reported infection rates of <2%. Overall, there is insufficient evidence to suggest that diabetic status or HgbA1c levels increase or decrease vulnerability to penile prosthesis infection.
DISCUSSION Treatment of ED with penile prosthesis placement results in a high degree of patient and partner satisfaction; however, although nearly all urologists manage patients with ED, national trends demonstrate that a minority of urologists perform penile prosthesis implantation.40 Concern regarding infectious complications, as well as concern over litigation for these complications, may discourage urologist utilization.41 Infectious adverse events represent one of the most devastating complications of prosthetic surgery. Device infection often requires explantation and leads to difficult reoperative procedures, further limiting patient quality of life.42 Reported infection rates vary widely across studies, and there are limited reliable data on factors that influence prosthetic infections. Our review of the literature suggests that infectious adverse events are rare, occurring in <5% of patients as reported in the majority of the available literature; many studies report no infectious complications. The body of literature suggests that there is a decreased rate of infection due to the advent of antibiotic and hydrophilic coatings. These modifications mainly work to inhibit bacterial attachment to the prosthesis in an effort to prevent biofilm formation.43 Although a significant reduction in infection rates with this technological advancement has been documented, infections can still occur. It is possible that prosthesis infections result from bacteria that escape these resistance mechanisms. Biofilm formation is a persistent problem that allows for bacterial resistance despite high concentrations of Sex Med Rev 2019;-:1e7
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Infectious Adverse Events Following Placement of Penile Prosthesis
antibiotic therapy.44 Moreover, infections caused by biofilms are often subclinical in nature.45 Limited data are available on biofilm prevention. Translational and basic science research focused on limiting infectious biofilms was outside the scope of this review, although future advancements in microbial science may help future biofilm prevention.46
Limitations The limitations of this study are inherent to any systematic review. Notably, the review is limited by the quality of evidence retrieved. All studies in our analysis were observational in design, including many case series and cohort studies. The overall body of evidence strength was Grade C. Moreover, penile prosthesis infection exists on a spectrum, and the reported infection rates were not uniform. Studies defined prosthesis infection as infection necessitating treatment with antibiotics or as infection requiring revision, or they did not specify their definition of infection. Many of the studies used patient information forms as a means of data acquisition, which are prone to error. In several instances, data were not extractable regarding specific subpopulations and infection risk. Especially in the setting of diabetic risk, exclusion of studies reporting on historical models limited our overall analysis. This review was completed in association with the American Urological Association Erectile Dysfunction Guideline panel. All articles analyzed were published prior to July of 2016. As such, articles published after this cutoff date are not included in this review. This pertains to the information about diabetic patients, as some recent studies have tried to further clarify the controversy on HgbA1c levels prior to implantation.47,48 Regardless, both of these studies are retrospective in nature and offer conflicting opinions about HgbA1c; thus, data about diabetic patients remain limited, without indicating a clear increase or decrease in vulnerability to infection following prosthesis placement. The literature is further limited by the use of historical controls to compare with new technology or surgical advancement. No study offered a randomized comparison or control group. It is possible, therefore, that this body of literature is influenced by reporting bias. Despite this limitation, the use of historical controls is likely the most feasible method to understand the evolution of infection rates associated with improved prosthesis technology and surgical techniques. Randomized studies with large sample sizes (>500 patients) and lengthy follow-up would be necessary to generate higher quality evidence. Given the overall low infection rate (<5%) and the data that strongly suggest a reduction in infection-related adverse events with the use of improved models and techniques, patients and surgeons may be reluctant to participate in control groups not offered these improvements.
impregnation of devices with antibiotic or hydrophilic materials, have greatly reduced the risk of infection. These device modifications, along with advances in surgical techniques, have further reduced infection rates in all patient populations undergoing penile prosthesis placement. In addition, the present body of literature does not conclusively support an increased or decreased risk of infection among diabetic patients or a discernable HgbA1c cutoff. Future research and clinical trials should focus on biofilm prevention to limit infectious events. Corresponding Author: Kevin T. McVary, MD-FACS, Department of Urology, Stritch School of Medicine, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153. Tel: 708-216-5405; Fax: 708-216-8991; E-mail: [email protected] Conflict of Interest: None. Funding: This review was performed as part of the 2018 American Urological Association Erectile Dysfunction Clinical Guidelines, with the support of the American Urological Association Clinical Guidelines Office, Linthicum, MD.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Kevin T. McVary; Lawrence Hakim; Hossein Sadeghi-Nejad (b) Acquisition of Data Martha M. Faraday (c) Analysis and Interpretation of Data Kevin T. McVary; Lawrence Hakim; Hossein Sadeghi-Nejad; Martha M. Faraday; Ryan Dornbier; Joseph Mahon; Grace Wegrzyn Category 2 (a) Drafting the Article Ryan Dornbier; Joseph Mahon; Grace Wegrzyn (b) Revising It for Intellectual Content Ryan Dornbier; Joseph Mahon; Grace Wegrzyn Category 3 (a) Final Approval of the Completed Article Ryan Dornbier; Joseph Mahon; Grace Wegrzyn; Hossein Sadeghi-Nejad; Lawrence Hakim; Martha M. Faraday; Kevin T. McVary
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Infectious Adverse Events Following the Placement of a Penile Prosthesis: A Systematic Review Joseph Mahon, MD,1 Ryan Dornbier, MD,1 Grace Wegrzyn, BS,2 Martha M. Faraday, PhD,3 Hossein Sadeghi-Nejad, MD,4 Lawrence Hakim, MD,5 and Kevin T. McVary, MD-FACS1
ABSTRACT
Introduction: Infection remains a prominent concern following penile implantation. Recognition of the risk factors for infection may help to guide surgeons toward reducing the risk of prosthetic contamination. Aim: To gain a further understanding of infectious adverse events following penile prosthesis, we performed a systematic literature review. Methods: As part of the 2018 American Urological Association Erectile Dysfunction Clinical Guidelines and with the support of the American Urological Association, we performed a comprehensive review of the PubMed, Embase, and Cochrane databases to search for eligible articles published between January 1, 1965, and July 20, 2016, to identify articles reporting infectious adverse events following prosthesis placement. Main Outcome Measure: The main outcome measure was infectious adverse events following penile prosthesis placement. Results: Ninety-one articles reporting infectious adverse events representing 97 study arms were identified. Prosthetic infection rates ranged from 0% to 24.6% across all series. Inflatable penile prostheses displayed a wider range (0e24.6%) than malleable devices (0e9.1%); the most frequently reported infection rate for inflatable devices was 5% or less. With the advent of device coatings and improved surgical techniques, infectious adverse events have decreased. Infections among diabetic patients also decreased throughout the reviewed body of literature, with the most recent series reporting rates consistent with those of non-diabetic patients. Furthermore, no glycosylated hemoglobin cutoff was found to infer increased or decreased risk of prosthesis infection. Conclusion: Overall penile prosthetic infectious adverse events have decreased as surgical techniques have improved and the use of antimicrobial coating has gained in popularity. These advances have demonstrated significant benefits for all patients, particularly diabetic patients who experience infection rates similar to those of non-diabetic patients in recent reports. Further technological advancements for the prevention of biofilm formation is warranted. Mahon J, Dornbier R, Wegrzyn G, et al. Infectious Adverse Events Following the Placement of a Penile Prosthesis: A Systematic Review. Sex Med Rev 2019;XX:XXXeXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Erectile Dysfunction; Penile Prosthesis; Infectious Adverse Event
Received May 22, 2019. Accepted July 11, 2019. 1
Center for Male Health, Department of Urology, Loyola University Stritch School of Medicine, Maywood, IL;
2
Loyola University Stritch School of Medicine, Maywood, IL;
3
Four Oaks Consulting, Inc, Berryville, VA;
4
Department of Urology, Hackensack University Medical Center, Hackensack, NJ, and Division of Urology, Rutgers New Jersey Medical School, Newark, NJ;
5
Department of Urology, Cleveland Clinic Florida, Weston, FL
Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.sxmr.2019.07.005
Sex Med Rev 2019;-:1e7
INTRODUCTION Some degree of erectile dysfunction (ED) is reported by 52% of male patients between 40 and 70 years of age, with a projected worldwide prevalence of 322 million men by the year 2025.1,2 Etiologies of ED encompass both organic and psychogenic causes, including advanced age, obesity, smoking, cardiovascular disease, diabetes mellitus, dyslipidemia, depression, and benign prostatic hyperplasia, which are wellknown risk factors and comorbid conditions.3,4 Regardless of cause, ED has a significant impact on sexual and overall quality of life.5e7 1
2
Over the last 50 years, treatment modalities for ED have expanded significantly. Pharmacologic therapies with phosphodiesterase-5 inhibitors, intracavernosal injections, and intraurethral alprostadil allow for non-surgical management; however, at least 30% of patients will experience failure or significant side effects with phosphodiesterase-5 inhibitors.8 Additionally, intracavernosal injections are associated with high discontinuation rates related to either patient dissatisfaction or cost.9,10 Alternatively, penile prosthesis placement represents the most definitive ED therapy given its ondemand functionality and high rates of satisfaction among patients and their partners.11,12 These quality of life improvements notwithstanding, penile prosthesis surgery is associated with complications. An infectious adverse event following penile prosthesis is a devastating complication and remains of paramount concern for the prosthetic surgeon. In most instances, a clinical device infection requires complete removal of the prosthesis with or without salvage reimplantation.13,14 Moreover, the subsequent corporal fibrosis makes device reimplantation more difficult and susceptible to adverse events, in addition to being associated with decreased patient satisfaction.15,16 Proposed risk factors for prosthesis infection include smoking status, diabetes, concurrent urinary tract infection or skin infection, prolonged operative time, revision surgery, and spinal cord injury.17,18 There has been significant attention given to preventing prosthesis infection with risk factor optimization, device modifications, and surgical techniques. To gain further understanding of current factors influencing infectious adverse events after penile prosthesis placement, we performed a systematic literature review.
METHODS This review was performed in conjunction with the 2018 American Urological Association (AUA) Erectile Dysfunction Guidelines,19 with support of the AUA Clinical Guidelines Office (Linthicum, MD). A systematic literature review was performed using the PubMed, Embase, and Cochrane databases to search for articles published between January 1, 1965, and July 20, 2016, using select key words to identify articles reporting on the treatment of ED with penile prostheses and outcomes data related to infectious adverse events. Titles and abstracts were reviewed for relevance, and preliminary exclusions were made. The relevant articles were retrieved in full-text form for a more detailed analysis, and additional exclusions were made after the full-text review. Articles reporting on preclinical data, animal models, devices of historical significance, devices no longer available, and reports no longer relevant to clinical practice were excluded. Studies were also excluded if outcomes data and adverse events were not reported, if infectious outcomes were not reported, if the reports duplicated the same patient populations, or if there was a small sample size (10 patients). All studies selected for analysis were assessed for quality. Systemic reviews were assessed using A Measurement Tool to Assess Systematic Reviews.20 Randomized controlled trials (RCTs) and controlled clinical trials were analyzed using the Cochrane risk-of-
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bias tool.21 Case-control studies and comparative observational studies were rated using the Newcastle-Ottawa Quality Assessment Scale.22 Due to their inherent variability, single-arm cohort studies were not assessed for quality. In addition to quality measures, each selected study was assigned a body of evidence strength in accordance with standard AUA guideline categorization: Grade A (well-conducted and highly generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data).23
RESULTS Database searches returned 267 articles, with 91 articles meeting inclusion criteria for full text review. All of the studies were observational in design, resulting in a body of evidence strength Grade C. Infectious outcomes were reported in 97 total study arms involving an inflatable penile prosthesis (IPP) or a malleable penile prosthesis (MPP), a variety of prosthesis subtypes, and patient populations (Table 1). In studies of the general ED population, infectious adverse events ranged from 0% to 24.6%.
IPP vs. MPP IPPs had a wider range of infectious adverse events (0e24.6%) than did MPPs (0e9.1%), and infectious adverse events for mixed IPP and MPP cohorts ranged from 0.5% to 13.7%. Of the 68 study arms that reported infection rates for IPPs, 7 arms (10.3%) reported rates of 0%, 26 arms (38.2%) reported rates of <2%, and 52 arms (76.5%) reported rates of <5%. Among 12 MPP cohorts, 4 study arms (33.3%) reported rates of <2%, and 6 study arms (50%) reported rates of <5%. In the remaining 11 cohorts reporting on mixed IPP and MPP cohorts, 2 (18.2%) reported rates of <2%, and 6 (54.5%) reported rates of <5%. Multiple studies have reported on the direct comparison of IPP models and MPP models, most in small case series. Bozkurt et al24 reported on men with the AMS 700CX, Ambicor, or Ultrex (n ¼ 118) (Boston Scientific; Marlborough, MA) or the AMS 600-650 (Boston Scientific) or Mentor Acu-Form (Mentor Worldwide; Irvine, CA) (n ¼ 139); follow-up durations were 34 and 52 months, respectively. The infection rate was higher in the inflatable group (4.2%) compared to the malleable group (1.44%), but this difference was not statistically significant. Additional information can be garnered from a comparison between the AMS 600 and AMS 700CX devices reported by Earle and colleagues.25 In their study, 57 men had the AMS 600 implanted, and 23 men had the AMS 700CX implanted; followup duration was not reported. Infection rates were 3.5% for the Sex Med Rev 2019;-:1e7
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Infectious Adverse Events Following Placement of Penile Prosthesis
Table 1. Infection rates by patient category, prosthesis type, and prosthesis subtype
Patient category
Prosthesis type
Prosthesis subtype
Study arms (n)
General population
Inflatable
AMS 700 Series AMS 700CX, Ambicor, or Ultrex AMS Ambicor or Coloplast Excel Mentor Alpha 1 and NB Coloplast Titan Other or multiple or unspecified inflatables Unspecified AMS Spectra malleable AMS 600-650 malleable AMS 600-650 or Mentor Acu-Form Other or multiple or unspecified malleable Mixed inflatable and malleable models AMS 700 series or Coloplast Titan AMS 700 series or Coloplast Titan Other or multiple or unspecified inflatables Mixed inflatable and malleable models AMS 600-650 malleable
27 1 1 11 8 19 1 1 6 1 4 11 1 1 2 1 1
Malleable
Diabetes Post-prostatectomy
Inflatable or malleable Inflatable Inflatable
Spinal cord injury
Inflatable or malleable Malleable
malleable model and 0% for the inflatable device. Altunkol et al26 reported on men with the AMS 700CX (n ¼ 16) or the AMS Spectra malleable (n ¼ 18); follow-up durations were 24.1 and 29.4 months, respectively. The infection rates were comparable in the inflatable group (6.3%) and the malleable group (5.6%). No study directly comparing IPP and MPP infectious adverse events was statistically significant. This suggests that the rates of infection for IPPs and MPPs are similar, with no increased risk of infection with either prosthesis type.
Device Coating The introduction of infection-retardant coating has drastically reduced the infection rate across device models. In a retrospective review comparing the AMS 700 with (n ¼ 58) and without (n ¼ 94) rifampin/minocycline (InhibiZone) impregnation, infection rates for the InhibiZone devices were significantly less (0%) compared to those for the non-InhibiZone devices (3.2%).27 Using patient information forms to compare AMS 700 series prostheses with InhibiZone (n ¼ 35,737) to those without InhibiZone (n ¼ 3,268) in terms of the need for revision as a result of infection (infection rates that did not require revision were not reported), Carson et al28 showed that the InhibiZone device was significantly less likely to require revision for infection (1.1%) compared to the same device without InhibiZone (2.5%). A hydrophilic coating on Coloplast devices (Coloplast Corp; Minneapolis, MN) also limits infection rates. Using patient information forms to compare the Coloplast Titan model with a hydrophilic coating (n ¼ 29,360) to the same model without a hydrophilic coating (n ¼ 7,031), Serefoglu and colleagues29 showed that the infection rate was significantly lower (1.4%) with the hydrophilic coating compared to no coating (4.6%). Eid and colleagues30 examined infection rates among men implanted with either the Sex Med Rev 2019;-:1e7
Infection rate (%) Minimum
Maximum
Mean
0.00 4.20 4.80 1.20 0.00 .10 5.60 5.60 1.40 1.44 0.00 .50 3.60 0.00 .81 3.30 8.30
11.80 4.20 4.80 24.60 9.00 15.90 5.60 5.60 9.10 1.44 8.90 13.70 3.60 0.00 1.10 3.30 8.30
3.42 4.20 4.80 4.57 2.86 4.88 5.60 5.60 4.93 1.44 4.08 5.92 3.60 0.00 0.96 3.30 8.30
Coloplast Titan model or the AMS 700 series (results not separated by model) that either had no infection-inhibiting coating (n ¼ 132) or had an infection-inhibiting coating (n ¼ 704). Infection rates for the non-coated group were 5.3% compared to 1.99% for the coated models. Notably, these studies are limited by their retrospective nature and utilization of historical controls for comparison. Only limited data directly compare the types of antibiotic coatings or solutions applied to devices. Dhabuwala and colleagues31 compared infection rates among the Coloplast Titan model coated with rifampin/gentamicin (n ¼ 81), the same model coated with vancomycin/gentamicin (n ¼ 181), and AMS 700 series models coated with InhibiZone (n ¼ 77). Infection rates were 0% for the rifampin/gentamicin group, 4.4% for the vancomycin/gentamicin group, and 1.3% for the AMS series with InhibiZone. The combined group of the Coloplast Titan coated with rifampin/gentamicin and the AMS series with InhibiZone saw an infection rate of 0.63%, suggesting a decreased infection rate with rifampin inclusion. Additional conclusions regarding the type of antibiotic coating cannot be reached, other than the direct comparisons made in this study. Further information regarding antibiotic solutions is limited, as many studies were preclinical in nature.
Surgical Technique and Revision Surgery The use of novel surgical techniques for infection reduction has been reported. The “no touch” technique describe by Eid et al30 in 2012 demonstrated improved infection rates among men implanted with a device that had an infection-retardant coating. In the “no touch” technique, the initial penoscrotal incision is made with dissection carried down to the level of Buck’s fascia. At this time, the procedure is halted, and all
4
surgical instruments used are considered contaminated and discarded. An additional plastic drape is placed over the retractor and surgical field, incised, and secured to the cut skin edge. The prosthesis implantation then proceeds through the cut drape. The group reported a reduction in infection rate from 1.99% without the technique to 0.46% with the technique; however, this study was not randomized and utilized historical controls for comparison to the “no touch” technique. Moreover, the results of this study have not been validated by additional surgeons. With respect to surgical site approach, no apparent difference in infection rates has been found. Garber and Marcus32 compared infection rates based on surgical approach among 360 men undergoing a first IPP placement. Infection rates were 2.9% for 139 infrapubic approaches and 0.9% for 221 scrotal approach cases; however, the difference was not statistically significant. Further information regarding surgical technique was garnered from Moncada et al.33 In their report, 100 patients were implanted with AMS 700 series devices with or without corporeal dilation, and the infection rate was identical at 2% between the 2 groups at 9-month follow-up. We noted that infectious adverse events increase in the setting of revision surgery. Jarow18 initially reported on infection rates for initial implantations among 114 men and for revision implants among 30 men. The infection rate was significantly higher for revision procedures (13.3%) compared to initial procedures (1.8%). Further information was reported by Abouassaly et al34 for 55 men undergoing explant of an inflatable prosthesis for mechanical failure and reimplant with an InhibiZone-coated model. At median follow-up of 32 months, 1 patient (1.8%) had developed an infection. Additional information can be gleaned from subgroup analyses from studies not directly comparing or evaluating revision surgeries. Using a variety of prosthesis models, Lotan and colleagues35 reported infection rates of 9.9% and 18.8% for primary and secondary implantation, respectively. According to Wilson and colleagues,36 infection rates among patients receiving IPPs with the InhibiZone coating were 0.33% for virgin implants (n ¼ 306) and 5.0% for revision implants (n ¼ 161).
Patient Population (Diabetics, Post-Prostatectomy, Spinal Cord Injury) Limited data are available offering direct comparison of specific patient populations. A single study reported on the use of the AMS 600 malleable prosthesis in patients with spinal cord injury. Of the 48 men followed for an average of 139 months, 4 (8.3%) developed infection. Two of the infectious events were managed conservatively, but the other 2 required device explantation.37 This study represents a small sample size; thus, specific conclusions regarding risk of penile prosthesis infection for men with spinal cord injury cannot be made. An area of regular concern for the prosthetic surgeon remains the influence of diabetes mellitus on infection rate. Few studies meeting the inclusion criteria specifically identified patients with
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diabetes as a comparison cohort. Several studies reporting on patients with diabetes were excluded because of a focus on only historically relevant devices. Wilson and colleagues38 followed 389 men (including 114 diabetic men) for 2 years after inflatable prosthesis implantation to evaluate whether elevated glycosylated hemoglobin (HgbA1c) was a risk factor for infection. Infections developed in 8.7% of diabetic men and 4.0% of non-diabetic men, a difference that reached borderline statistical significance (P ¼ .06); however, HgbA1c levels were not significant predictors of infection for diabetic or non-diabetic men. In their investigation of surgical approaches, Garber and Marcus32 found infection rates of 2.8% among diabetic patients and 0.9% among non-diabetic patients; this difference also was not statistically significant. In a large case series of 2,347 IPPs reported by Eid et al30 (discussed earlier with regard to the “no touch” technique for antibiotic-coated devices), 41% of the population had a diagnosis of diabetes. Infection rates were 0.6% for the diabetic population and 1.5% for the non-diabetic population. Christodoulidou and Pearce39 conducted a systematic review analyzing case series using historical and current devices. Most reports of higher infection rates were among historical devices, but large modern case series using devices with antibiotic coatings reported infection rates of <2%. Overall, there is insufficient evidence to suggest that diabetic status or HgbA1c levels increase or decrease vulnerability to penile prosthesis infection.
DISCUSSION Treatment of ED with penile prosthesis placement results in a high degree of patient and partner satisfaction; however, although nearly all urologists manage patients with ED, national trends demonstrate that a minority of urologists perform penile prosthesis implantation.40 Concern regarding infectious complications, as well as concern over litigation for these complications, may discourage urologist utilization.41 Infectious adverse events represent one of the most devastating complications of prosthetic surgery. Device infection often requires explantation and leads to difficult reoperative procedures, further limiting patient quality of life.42 Reported infection rates vary widely across studies, and there are limited reliable data on factors that influence prosthetic infections. Our review of the literature suggests that infectious adverse events are rare, occurring in <5% of patients as reported in the majority of the available literature; many studies report no infectious complications. The body of literature suggests that there is a decreased rate of infection due to the advent of antibiotic and hydrophilic coatings. These modifications mainly work to inhibit bacterial attachment to the prosthesis in an effort to prevent biofilm formation.43 Although a significant reduction in infection rates with this technological advancement has been documented, infections can still occur. It is possible that prosthesis infections result from bacteria that escape these resistance mechanisms. Biofilm formation is a persistent problem that allows for bacterial resistance despite high concentrations of Sex Med Rev 2019;-:1e7
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Infectious Adverse Events Following Placement of Penile Prosthesis
antibiotic therapy.44 Moreover, infections caused by biofilms are often subclinical in nature.45 Limited data are available on biofilm prevention. Translational and basic science research focused on limiting infectious biofilms was outside the scope of this review, although future advancements in microbial science may help future biofilm prevention.46
Limitations The limitations of this study are inherent to any systematic review. Notably, the review is limited by the quality of evidence retrieved. All studies in our analysis were observational in design, including many case series and cohort studies. The overall body of evidence strength was Grade C. Moreover, penile prosthesis infection exists on a spectrum, and the reported infection rates were not uniform. Studies defined prosthesis infection as infection necessitating treatment with antibiotics or as infection requiring revision, or they did not specify their definition of infection. Many of the studies used patient information forms as a means of data acquisition, which are prone to error. In several instances, data were not extractable regarding specific subpopulations and infection risk. Especially in the setting of diabetic risk, exclusion of studies reporting on historical models limited our overall analysis. This review was completed in association with the American Urological Association Erectile Dysfunction Guideline panel. All articles analyzed were published prior to July of 2016. As such, articles published after this cutoff date are not included in this review. This pertains to the information about diabetic patients, as some recent studies have tried to further clarify the controversy on HgbA1c levels prior to implantation.47,48 Regardless, both of these studies are retrospective in nature and offer conflicting opinions about HgbA1c; thus, data about diabetic patients remain limited, without indicating a clear increase or decrease in vulnerability to infection following prosthesis placement. The literature is further limited by the use of historical controls to compare with new technology or surgical advancement. No study offered a randomized comparison or control group. It is possible, therefore, that this body of literature is influenced by reporting bias. Despite this limitation, the use of historical controls is likely the most feasible method to understand the evolution of infection rates associated with improved prosthesis technology and surgical techniques. Randomized studies with large sample sizes (>500 patients) and lengthy follow-up would be necessary to generate higher quality evidence. Given the overall low infection rate (<5%) and the data that strongly suggest a reduction in infection-related adverse events with the use of improved models and techniques, patients and surgeons may be reluctant to participate in control groups not offered these improvements.
impregnation of devices with antibiotic or hydrophilic materials, have greatly reduced the risk of infection. These device modifications, along with advances in surgical techniques, have further reduced infection rates in all patient populations undergoing penile prosthesis placement. In addition, the present body of literature does not conclusively support an increased or decreased risk of infection among diabetic patients or a discernable HgbA1c cutoff. Future research and clinical trials should focus on biofilm prevention to limit infectious events. Corresponding Author: Kevin T. McVary, MD-FACS, Department of Urology, Stritch School of Medicine, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153. Tel: 708-216-5405; Fax: 708-216-8991; E-mail: [email protected] Conflict of Interest: None. Funding: This review was performed as part of the 2018 American Urological Association Erectile Dysfunction Clinical Guidelines, with the support of the American Urological Association Clinical Guidelines Office, Linthicum, MD.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Kevin T. McVary; Lawrence Hakim; Hossein Sadeghi-Nejad (b) Acquisition of Data Martha M. Faraday (c) Analysis and Interpretation of Data Kevin T. McVary; Lawrence Hakim; Hossein Sadeghi-Nejad; Martha M. Faraday; Ryan Dornbier; Joseph Mahon; Grace Wegrzyn Category 2 (a) Drafting the Article Ryan Dornbier; Joseph Mahon; Grace Wegrzyn (b) Revising It for Intellectual Content Ryan Dornbier; Joseph Mahon; Grace Wegrzyn Category 3 (a) Final Approval of the Completed Article Ryan Dornbier; Joseph Mahon; Grace Wegrzyn; Hossein Sadeghi-Nejad; Lawrence Hakim; Martha M. Faraday; Kevin T. McVary
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47. Habous M, Tal R, Tealab A, et al. Defining a glycated haemoglobin (HbA1c) level that predicts increased risk of penile implant infection. BJU Int 2018;121:293-300. 48. Canguven O, Talib R, El Ansari W, et al. Is HbA1c level of diabetic patients associated with penile prosthesis implantation infections? Aging Male 2018;9:1-6.