Defining a glycated haemoglobin (HbA1c) level that predicts increased risk of penile implant infection

Abstract

Objectives

To re-evaluate the role of diabetes mellitus (DM) as a risk factor for penile implant infection by exploring the association between glycated haemoglobin (HbA1c) levels and penile implant infection rates and to define a threshold value that predicts implant infection.

Patients and Methods

We conducted a multicentre prospective study including all patients undergoing penile implant surgery between 2009 and 2015. Preoperative, perioperative and postoperative management were identical for the entire cohort. Univariate analysis was performed to define predictors of implant infection. The HbA1c levels were analysed as continuous variables and sequential analysis was conducted using 0.5% increments to define a threshold level predicting implant infection. Multivariable analysis was performed with the following factors entered in the model: DM, HbA1C level, patient age, implant type, number of vascular risk factors (VRFs), presence of Peyronie’s disease (PD), body mass index (BMI), and surgeon volume. A receiver operating characteristic (ROC) curve was generated to define the optimal HbA1C threshold for infection prediction.

Results

In all, 902 implant procedures were performed over the study period. The mean patient age was 56.6 years. The mean HbA1c level was 8.0%, with 81% of men having a HbA1c level of >6%. In all, 685 (76%) implants were malleable and 217 (24%) were inflatable devices; 302 (33.5%) patients also had a diagnosis of PD. The overall infection rate was 8.9% (80/902). Patients who had implant infection had significantly higher mean HbA1c levels, 9.5% vs 7.8% (P < 0.001). Grouping the cases by HbA1c level, we found infection rates were: 1.3% with HbA1c level of <6.5%, 1.5% for 6.5–7.5%, 6.5% for 7.6–8.5%, 14.7% for 8.6–9.5%, 22.4% for >9.5% (P < 0.001). Patient age, implant type, and number of VRFs were not predictive. Predictors defined on multivariable analysis were: PD, high BMI, and high HbA1c level, whilst a high-volume surgeon had a protective effect and was associated with a reduced infection risk. Using ROC analysis, we determined that a HbA1c threshold level of 8.5% predicted infection with a sensitivity of 80% and a specificity of 65%.

Conclusion

Uncontrolled DM is associated with increased risk of infection after penile implant surgery. The risk is directly related to the HbA1c level. A threshold HbA1c level of 8.5% is suggested for clinical use to identify patients at increased infection risk.

Introduction

Diabetes mellitus (DM) is a well-known risk factor for erectile dysfunction (ED). It has been estimated that ED occurs in >50% of men with DM and diabetics are four-times more likely to develop ED than the general population [1]. ED in men with DM is multi-factorial resulting from autonomic neuropathy, cavernosal arteriosclerosis, and cavernosal smooth muscle collagenisation due to advanced glycation end-products [2]. Thus diabetics with ED often have more severe ED and are more resistant to treatment compared with nondiabetic ED [3].

In a large population cohort study, Walsh et al. [4] showed that diabetic men are more than twice as likely to undergo penile prosthesis surgery. In the recently published Prospective Registry of Outcomes With Penile Prosthesis for Erectile Restoration (PROPPER) study, including men from 11 medical centres in North America, it was shown that >20% of men undergoing penile prosthesis surgery were diabetics [5].

Implant infection is a devastating complication of penile implant surgery. Large variations in implant infections rates exist in the literature, ranging from 0.6% to 8.9% for primary procedures with most studies ranging between 1% and 4%. The incidence reaches 13% for re-implant procedures and an even higher incidence of 21.7% has been reported when penile reconstruction accompanied penile implant insertion [5–8].

The role of glycaemic control in predicting implant infection has been debated in the literature. In 1992, Bishop et al. [8] showed an increased risk of penile implant infection in men with uncontrolled DM and glycated haemoglobin (HbA1c) levels >11.5%. In 1998, Wilson et al. [9] failed to demonstrate a predictive role of preoperative HbA1c levels in identifying men at increased penile implant infection risk.

The present study aimed at re-evaluating the role of DM as a risk factor for penile implant infection by exploring the association between serum HbA1c level and penile implant infection risk; and to define a HbA1c threshold level that predicts an increased rate of penile implant infection.

Patients and Methods

The present study is based on a prospectively built, large, multicentre database including all cases of penile implant surgery performed in the years 2009–2015. Four private centres specialised in urology and andrology participated in the study. The data collected for each procedure included: identification of each centre and surgeon, patient data (e.g. medical and sexual history), indication for surgery, procedure-related data (e.g. early and late complications). Our database included diabetic and non-diabetic men. Peyronie’s disease (PD) was diagnosed primarily clinically by identifying penile plaque and/or deformity during examination. Then this was confirmed with Duplex ultrasonography. All patients signed a detailed consent before surgery.

Penile Implant Surgery

Patients were counselled about the risks and benefits of implant surgery, and the differences between inflatable and malleable devices including cost, a significant consideration for our patients, as implant surgery is not covered by insurance. The standards of infection control protocols for implant surgery are applied in our centres. We used gentamycin and rifampicin in saline as the irrigation solution. Most of the devices were antibiotic coated (Titan®/Genesis®; Coloplast Coloplast Ltd., Nene Hall, Peterborough, UK), whilst two devices were AMS 700™ LGX InhibiZone® (Boston Scientific, Marlborough, MA, USA). Details of the models used are shown in Table 1.

Table 1.

The penile prosthesis models (manufacturers) and frequency of use in the present study.

Penile prosthesis model (manufacturer)	N (%)	Cumulative %
Ambicor AMS™ (Boston Scientific)	9 (1.0)	1
AMS 700™ LGX (Boston Scientific)	2 (0.2)	1.2
Genesis® (Coloplast Ltd.)	661 (73.3)	74.5
Promedon Tube® (Promedon, Cordoba, Argentina)	4 (0.4)	74.9
Spectra™ (Boston Scientific)	18 (2.0)	76.9
Titan® OTR (Coloplast Ltd)	208 (23.1)	100
Total	902 (100)

Patients were prepared preoperatively as follows: they were instructed to bathe nightly with antibacterial soap for the three nights before surgery; shaving was done in the operating room; i.v. gentamycin was administered at 3 mg/kg 2 h preoperatively and ceftriaxone 1 g was given at anaesthesia induction; amoxicillin/clavulanate potassium 500 mg twice daily was given for 2 weeks after surgery. All operations were performed through a median raphe incision (malleable devices) or a transverse scrotal approach (inflatable devices). The reservoir was routinely placed in the space of Retzius, unless the medical history precluded this (prior inguinal hernia repair surgery, renal transplant patients) or difficulty was encountered creating such a space in men following radical pelvic surgery. Patients remained in hospital for a single night and were followed as follows: they were seen in the outpatient clinic twice a week for the first 2 weeks and weekly for weeks 3 and 4, and every 3 months until lost to follow-up. Infection was diagnosed when one or more of the following signs existed: scrotal fluctuance, pump fixation to skin, purulent drainage, and device erosion. Infection diagnosis was established based on clinical judgment and all infections were confirmed at the time of surgery using bacterial and fungal cultures.

Statistical Analysis

The serum HbA1c level was analysed as a continuous variable and as ordinal variable after grouping subjects according to HbA1c level: <6.5%, 6.5–7.5%, 7.5–8.5%, 8.5–9.5% and >9.5%. Poor glycaemic control was defined as a HbA1c level of >8% [10]. The occurrence of implant infection was analysed as a dichotomous variable (yes/no). For the purpose of the study, a high-volume surgeon was defined as a surgeon who had performed ≥30 penile implant procedures in the study period.

Descriptive statistics were used to characterise the study group. Implant infection predictors were analysed: the t-test was used for continuous variables and the chi-squared test was used for dichotomous or ordinal predictors. A multivariate analysis was performed to look for significant predictors of penile implant infection controlling for all other variables. Factors entered into the multivariable model included: patient age, duration of ED, duration of DM, HbA1c level (as defined above), surgeon, number of implant operations performed by each surgeon, centre at which the operation was performed, duration of the operation, presence of PD, patient body mass index (BMI), number of vascular risk factors (VRFs) other than DM.

A receiver operating characteristic (ROC) curve is a graphical plot illustrating the diagnostic ability of a binary (high/low) classifier system, created from a continuous variable (HbA1c) as its discrimination threshold is varied. Utilising the ROC curve, we aimed at:

1. Evaluating possible variables to serve as binary classifiers

2. Selecting the best variable of all

3. Selecting the statistically ideal threshold point for the selected variable

4. Incorporating clinical considerations and clinically determining the threshold point.

A ROC curve was constructed to search for an optimal serum HbA1c level threshold that predicts infection with optimal sensitivity and specificity. For all comparisons, a P ≤ 0.05 was considered statistically significant.

Results

Study Population

In the study years, 2009–2015, 902 penile implant procedures were performed and included in our database. The mean patient age was 56.6 years. The mean HbA1c level was 8.0%, with 81% of men having a HbA1c level of >6%. In all, 685 (76%) implants were malleable and 217 (24%) were inflatable devices; 302 (33.5%) patients also had a diagnosis of PD. The procedures were performed by 16 different surgeons at eight different medical facilities. In all, 735 (91.6%) procedures were performed by high-volume surgeons, re-do surgeries accounted for only 19 (2.1%) procedures and the remaining 883 (97.9%) were primary implants. The patients’ demographic data and characteristics are outlined in Table 2. Of the study population, 674 patients (74.8%) were diabetic and of these 553 (61.3% of the total population) had poor glycaemic control. The distribution of the patients by their glycaemic control according to their serum HBA1c level is depicted in Fig. 1. The results of the cultures of infected implants showed that Staphylococcus epidermidis was the most organism encountered in 42% of patients, Escherichia coli was encountered in 19%, Pseudomonas in 16%, and the remaining were Staphylococcus aureus and Candida.

Table 2.

The patients’ characteristics.

Characteristic	Value
Age, years, mean (sd; range)	56.6 (10.6; 23.0–82.0)
BMI, kg/m2, mean (sd; range)	30.2 (5.1; 16.0–49.0)
Number of VRFs, n (%)
0	88 (11.3)
1–2	477 (61.3)
≥3	214 (27.4)
VRF, n (%)
Smoking	262 (32.7)
Dyslipidaemia	352 (43.9)
Diabetes	674 (74.8)
Hypertension	256 (32.8)
BMI >30 kg/m2	466 (51.7)
Concomitant PD, n (%)	302 (33.5)
HbA1c, %, mean (sd; range)	8.0 (1.7; 4.6–14.5)
HbA1c ≥7.5%, n (%)	553 (61.3)
Follow-up, months, mean (sd; range)	28.3 (16.9; 0.4–78.3)

Fig. 1.

HbA1c (%) level distribution in the study population.

Predictors of Penile Implant Infection

The mean (range) operative time was 35 (18–118) min for a malleable device and 77 (44–143) min for an inflatable device. Of the 902 penile implant insertion procedures, 80 implants became infected, yielding an infection rate of 8.9%. The infection rate for the malleable devices was 8.9% and 9.1% for the inflatable implants (P = 0.639; Table 3). The mean (sd) HbA1c level in the infection group was 9.5 (1.4)% compared to 7.8 (1.7)% in the non-infected group (P < 0.001). The results of univariate analysis (independent samples t-test for continuous variables and chi-squared test for dichotomous/categorical variables) searching for possible predictors for the occurrence of postoperative implant infection are presented in Table 4. According to the results, a higher BMI, greater number of VRFs, higher serum HbA1c level, a diagnosis of PD, and performance of the procedure by a low-volume surgeon were significant predictors of penile implant infection. On multivariable analysis (Table 5), a diagnosis of PD, higher serum HbA1c level, higher BMI, and performance of the procedure by a low-volume surgeon remained significant independent predictors of penile implant infection.

Table 3.

Infection rates stratified by prosthesis type.

Infection	Prosthesis type
	Malleable	Two-piece inflatable	Inflatable	Total
No
N	624	9	189	822
% Of all uninfected prostheses	75.90	1.1	23.00	100
% Within prosthesis type	91.10	100	90.90	91.10
Yes
N	61	0	19	80
% Of all infected prostheses	76.2	0	23.80	100
% Within prosthesis type	8.90	0	9.10	8.90
Total
N	685	9	208	902
% Of all prostheses	75.90	1.00	23.10	100
% Within prosthesis type	100	100	100	100

Table 4.

Univariate analysis predictors of penile implant infection.

Variable	No implant infection	Implant infection	P
Age, years, mean (sd)	56.5 (10.6)	57.5 (10)	NS
BMI, kg/m2, mean (sd)	30.0 (5.1)	31.8 (5.6)	0.005
Patients with >2 VRFs, %	25.70	45.10	<0.001
Patients with HbA1c ≥8.5%, %	33.60	77.50	<0.001
Cases performed by low-volume surgeon, %	7.20	20.00	<0.001
Concomitant PD, %	31.40	55.00	<0.001

Table 5.

Multivariable analysis: predictors of penile implant infection.

Variable	Odds ratio (95% CI)	P
PD	2.51 (1.5–4.2)	<0.001
HbA1c ≥8.5%	7.34 (4.09–13.16)	<0.001
BMI (per 5 kg/m2 increase)	1.34 (1.05–1.71)	0.02
Low-volume surgeon	2.47 (1.24–4.93)	0.01

ROC Curve Analysis

In the present study, our predicted event was ‘infection’ and we searched for possible variables that we could use as binary classifiers: age, number of VRFs, BMI, HbA1C%. A change in the binary classifier value (low/high) should change the risk of eventual infection. The greater the area under the curve – the greater the impact of the variable (Fig. 2 and Table 6).

Fig. 2.

ROC curve of possible binary classifiers: age, number of VRFs, BMI, HbA1C%.

Table 6.

Area under the ROC curve.

Test result variable	Area (se)	Asymptotic significance (95% CI)
Age	0.543 (0.035)	0.239 (0.473–0.612)
Number of VRFs	0.679 (0.029)	<0.001 (0.622–0.736)
BMI	0.586 (0.038)	0.019 (0.511–0.660)
HbA1c	0.783 (0.025)	<0.001 (0.735–0.832)

We further sought to use the serum HbA1c level as a tool to predict a clinically significant increased risk of postoperative penile implant infection. For that purpose, we searched for a serum HbA1c level threshold point above which the risk of implant infection rises considerably with consideration of this threshold value’s specificity and sensitivity. To find this ideal HbA1c threshold point, we constructed a ROC curve and found that the use of a serum HbA1c threshold level of 8.5% represented a threshold level with a sensitivity of 80% and a specificity of 65% to predict infection. Statistically, the point marked with a blue star (Fig. 3) is the ideal point to use as a threshold value for the HbA1c variable, if we wish to use HbA1c as a binary classifier and if we wish to determine a value above which infection risk is increased with high sensitivity and specificity. According to the ROC coordinate table, this point represents a HbA1c level of 8.5% and using this point as a threshold, can predict infection with a high sensitivity of 0.8 and a good specificity of 0.65 (1-specificity of 0.35). If we move to the left of this point, the sensitivity declines sharply, thus weakening HbA1c as a binary classifying tool level (Fig. 3).

Fig. 3.

ROC curve. The starred point corresponds to a serum HBA1c threshold level of 8.5% with a sensitivity of 80% and specificity of 64.6% to predict penile implant infection.

Discussion

DM is a major risk factor for the development of ED. Mechanisms causing ED in DM are multifactorial and often lead to resistance to current therapy. Systemic effects of hyperglycaemia and testosterone deficiency contribute to the development of impaired vasodilatory signalling, smooth muscle cell hypercontractility, and veno-occlusive disorder in diabetics [11]. Diabetic ED is generally more severe and hence more resistant to less invasive therapy compared with non-diabetic ED [3]. Published data has shown that diabetic men have more than double the risk of undergoing penile prosthesis surgery [4].

Despite >40 years of penile implant use, infection remains a significant clinical problem [12]. Penile implant infection leads to increased patient morbidity, patient hospital readmission, prolonged surgery-related hospital stay, prolonged use of broad spectrum antibiotics, and implant removal [13]. Grewal et al. [14] surveyed patients discharge and re-visit data in a contemporary series of penile implant surgeries and found that infectious complications were the most common reason for reoperation. Whilst Lledó-García et al. [15] reported high patient and partner satisfaction after both primary and replacement surgery. Reoperation is an undesirable event as it is associated not only with added morbidity but also with inferior results, including reduced implant survival. Lotan et al. [16] reported 5-year prosthesis survival rates of 71% vs 42% and 10-year rates of 60% vs 35% for primary and secondary surgery, respectively.

Technological advances, such as antibiotic coating and hydrophilic surfaces, have improved implant infection rates, but have not completely eliminated infectious complications [17]. Infection rates in contemporary series are low [17]. Infection rates in diabetic patients are low as well, ~1.5%, a rate that is not clinically different compared to the infection rate in non-diabetics [7,18]. However, DM is a heterogeneous disease in its severity: whilst some patients are well controlled and do not have significant end-organ damage, others have severe manifestations, e.g. ED, cardiovascular disease, nephropathy, retinopathy, neuropathy. With advances in DM diagnosis and treatment, and the development of highly effective DM medications, it is difficult to recruit a large diabetic patient population undergoing penile implant surgery, especially one with poorly controlled DM. This difficulty has hindered studying the effect of DM control on penile implant surgery outcomes in general and infection risk in particular. The present study is relatively unique because it was performed in a geographic location notorious for a high rate of DM and a high rate of poorly controlled diabetics.

Our present study group enabled us to compare infection rates across a wide spectrum of DM control levels. The serum HbA1c level is currently the best available marker for DM long-term control, it is commonly used in current DM studies and it has been shown to be related to the incidence of various DM-related complications [19,20]. Therefore, we used HbA1c level to stratify our patient population into subgroups, according to their DM-control status. One third of our patients were diagnosed with PD, which was a predictor in multivariable analysis. We think that the prolongation in the procedure, and the extra manoeuvres needed in some patients with PD are possible contributors to the increase in infection rate in those patients.

In 1992, Bishop et al. [8] reported an 18-month prospective study of 90 patients undergoing penile prosthesis implantation. Of 90 patients, five (5.5%) had a periprosthetic infection requiring explantation and all infections occurred in the 32 diabetics (36%) in the population (P < 0.009). Of the 32 diabetics, 13 (41.1%) were poorly controlled with time as demonstrated by a serum HbA1c level of >11.5% and four of the infections occurred in this group. Of the 19 remaining controlled diabetics (HbA1c level of <11.5%) only one infection occurred. Therefore, infection occurred in 31% of the poorly controlled vs 5% of the adequately controlled patients (P < 0.001). Contrasting with the Bishop et al. [8] study, Wilson et al. [9] reported their results in a larger number of patients (389, including 114 diabetics). The risk of infection was statistically analysed for diabetics vs non-diabetics, and HbA1c values of > and <11.5%. Prosthesis infections developed in 10 diabetics (8.7%) and 11 non-diabetics (4.0%). There was no statistically significant increased infection risk with increased levels of HbA1c amongst all patients or only amongst the diabetics. We think that using a serum HbA1c level of 11.5% as a threshold for adequately controlled DM is not reasonable, as it is very high. Moreover, the relatively small number of patients who developed infection was another significant limitation.

Interestingly, in the present study, we found that in poorly controlled diabetics’ infection risk was increased and directly associated with serum HbA1c level. Whilst infection risk was as low as 1.3% when the HbA1c level was <6.5%, it increased in a step-wise fashion in association with HbA1c level to reach 22.4% in diabetics with a HbA1c level of >9.5%. This finding of increased risk has important clinical implications: preoperatively, when discussing penile implant complications, diabetic men should be informed that their infection risk is higher, depending on their HbA1c level. Accurate assessment of infection risk may even change a patient’s decision to opt for penile implant surgery. Our present study provides an indication that better DM control and successful lowering of HbA1c level may reduce infection risk in a given patient, a hypothesis that needs to be confirmed in future carefully designed studies.

Although statistically, a threshold serum HbA1c level of 8.5% is reasonable, considering its sensitivity and specificity, we need to incorporate clinical considerations too. Looking at the present results, the infection rate was as low as 1.3—1.5% when the HbA1c level was ≤7.5% but sharply rose to 6.5%, 14.7% and 22.4% when the HbA1c levels rose to 7.6–8.5%, 8.6–9.5%, and >9.5%, respectively. Incorporating this information, we learn that although statistically the ideal HbA1c threshold point is 8.5%, clinically we cannot allow such a high infection rate and we should choose a lower threshold point of 7.5%. With the help of the ROC coordinate table (Table 6) we can locate the red star which represents the HbA1c threshold point of 7.5% (Fig. 4). According to the table, this point can determine increased infection risk with very high sensitivity of 0.94 but low specificity of only 0.44 (1-specificity: 0.56). Selecting this lower HbA1c threshold point, 7.5% instead of 8.5%, will yield safer surgeries with lower risk of infection (high sensitivity), but more patients will not qualify for the surgery because their HbA1c level is >7.5%, which is the implications of a low specificity. One of the means for defining an optimal threshold value is the generation of a ROC curve. Our present ROC curve showed the optimal threshold to predict infection was a HbA1C value of 8.5% with a sensitivity of 80% and a specificity of 65%. Looking at our present results, infection rate is as low as 1.3—1.5% when HbA1c is <7.5% but sharply rises to 6.5%, 14.7% and 22.4% when HbA1c levels rise to 7.6–8.5%, 8.6–9.5% and >9.5%, respectively. Whilst these latter data are crucial to the preoperative discussion the surgeon has with the patient, we suggest that the surgeon should consider not proceeding with an implant procedure in a diabetic with a HbA1C level of > 8.5%. A HbA1c level of >7.5% does not necessarily mean infection, but if we consider it as the threshold, we will prevent many patients from having an implant. To further illustrate this point, we can take it to the extreme: if we select a HbA1c level threshold 4.0%, we will have excellent infection rate control but hardly any patients to operate on.

Fig. 4.

ROC with a serum HBA1c threshold level of 7.5%.

The present study has some important limitations: it is based on a prospectively built database rather than a randomised controlled study comparing infection risk between uncontrolled diabetics and diabetics who initially had high HbA1c level and managed to lower their HbA1c levels to various levels. This fact has prevented us from decisively concluding that lowering HbA1c level preoperatively will decrease infection risk. Until better evidence becomes available, we think it is a reasonable policy to lower the HbA1c level before penile implant surgery. Despite this, the present study has some clinically important strengths: it is the first study exploring diabetic control as a risk factor for penile implant infection using a unique population with wide range of glycaemic control. Our present results are based on a large study group, recruited from several medical centres and managed by several surgeons. Robust statistical analysis has been employed to define a threshold HbA1c level of 8.5% as a target level at which to defer implant surgery and have the patient improve his glycaemic control.

Conclusion

Uncontrolled DM is associated with an increased risk of infection after penile implant surgery. The risk is directly related to the HbA1c level. A threshold HbA1c level of 8.5% is suggested for clinical use to identify patients at clinically significant increased infection risk.

Abbreviations:

BMI

body mass index

DM

diabetes mellitus

ED

erectile dysfunction

HbA1c

glycated haemoglobin

PD

Peyronie’s disease

ROC

receiver operating characteristic

VRF

vascular risk factor