International Journal of Antimicrobial Agents 38S (2011) 58–63

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Antibiotic prophylaxis in urological surgery, a European viewpoint夽 Magnus Grabe ∗ Department of Urology, Skåne University Hospital, University of Lund, S-20502 Malmö, Sweden

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Keywords: Surgical site infection Wound infection Urinary tract infection Antibiotic prophylaxis

a b s t r a c t Surgical site infections (SSI) including urinary tract infections (UTI) cause a significant morbidity in urological surgery. Antibiotic prophylaxis is one of several factors impacting on infection rates. Antibiotic prophylaxis is relevant only for clean and clean-contaminated operations and in the absence of bacterial growth in the urine. Strict classification of urological procedures is lacking, but a proposal is presented elsewhere. Only TURP and transrectal core prostate biopsy are well documented. The present review confirms that there is a lack of hard data, insufficient consistency in classification and definitions, and that new well-powered RCT and large multicentre quality cohort studies including risk factor analysis are necessary to improve recommendations for antibiotic prophylaxis in urologic surgery. © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Summary of recommendations The summary of recommendations are given in Table 1. The reader will find a paradox in the level of evidence and the policy recommended. The reasons are therefore explained for each procedure in its respective section. 2. Introduction This manuscript was published originally in Urogenital Infections as a section of a chapter on prevention of infections associated with urological surgery (ch 12), antibiotic prophylaxis being one of several preventive measures. It has thus to be seen as an article integrated with the associated manuscript on preoperative assessment of the patient giving a tentative classification of urological procedures. The present article focus on what is known and evidence-based information on antibiotic prophylaxis in most common urological procedures. The use of antibiotics in urologic surgery has been controversial for decades [1,2]. Over the same period of time, surgical procedures and interventions have evolved remarkably from high-invasive open to low-invasive surgery due to a fascinating improvement of technologies and instruments. Also, medical treatment has replaced surgery in a substantial number of situations and in this way modified the profile of patients undergoing surgery.

The basic principle of antibiotic prophylaxis is to protect the patient undergoing surgery against undesirable infectious complications by lowering the bacterial burden. Antibiotic prophylaxis is applicable for clean and clean-contaminated operations. For the urinary tract, antibiotic prophylaxis implies the absence of detectable bacterial growth in urine (<104 CFU/ml). In clean operations, the urinary tract is not opened. In clean-contaminated operations, the urinary tract is opened and, in case of urinary diversion, the intestinal tract, implying an increased bacterial burden. In the case of bacterial growth and surgery associated with opening of the bowel with spillage – contaminated operations – an individual treatment strategy is prescribed [3]. Two types of infections dominate urologic surgery: (1) urinary tract infection (UTI), a space or organ infection, associated with both endoscopic, endoluminal interventions and open or laparoscopic surgery, mostly coinciding with catheter and stent placement or undetected harboured bacterial load and (2) wound infection after open and laparoscopic surgery. Furthermore, a third form of infection is observed in terms of infection of the male genital system (prostatitis, epididymitis and orchitis). A fourth form of infection, blood-stream-borne sepsis, resulting from urologic instrumentation, is feared by patients and urologists, and is far from negligible accounting for 10–12% of healthcare-associated infections (HAI) in urologic wards [4]. 3. Aim

夽 This manuscript was originally published in: Naber KG, Schaeffer AJ, Heyns CF, Matsumoto T, Shoskes DA, Bjerklund Johansen TE, editors. Urogenital Infections. European Association of Urology–International Consultation on Urological Diseases, 1st ed. Arnhem, The Netherlands; 2010, ISBN:978-90-79754-41-0. ∗ Tel.: +46 40 33 18 25; fax: +46 40 33 70 49. E-mail address: [email protected]

The present report focuses on the most frequent diagnostic and therapeutic urologic interventions (Table 1) and results from a systematic review. It is out of range to be comprehensive and cover all specific or special procedures as several of these have never been studied. Also paediatric urologic surgery is not covered.

0924-8579/$ – see front matter © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2011.09.008

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Table 1 Summary of recommendations for antibiotic prophylaxis (ABP) per type of procedure. Type of procedure

Level of recommendation

Remarks

Diagnostic procedures Cystoscopy

No systematic ABP (GoR A)

Urodynamic study

No systematic ABP (GoR A)

Core prostate biopsy

To all patients (GoR A)

Low frequency of infections Contradictory findings Low frequency of infections Contradictory findings Single dose to all low-risk patients (GoR A) prolonged in high-risk patients (GoR C) No available studies

URS diagnostic Therapeutic procedures TURB

No systematic ABP (GoR C)

TURP Shock-wave lithotripsy (ESWL)

As for cystoscopy in standard small TURB (GoR C) Consider in large tumours (GoR C) All patients (GoR A) No systematic ABP (GoR A)

Ureteroscopic stone management

To all patients (GoR B)

Percutaneous stone management

To all patients (GoR B)

Open/lap nephrectomy Open/lap nephroureterectomy

No systematic ABP (GoR C) To all patients (GoR C)

PUJ repair Open/lap bladder resection, ureteral repair Open/lap prostatectomy Cystectomy with urine deviation

To all patients (GoR C) To all patients (GoR C) To all patients (GoR B) To all patients (GoR B)

Surgery for hydrocele and spermatocele Prosthetic procedures

No systematic ABP (GoR B) To all patients (GoR B)

No concern of tumour burden in studies Well documented Low frequency of infections Contradictory findings Simple mid and distal stones Complex, proximal stones as for PCNL Single dose to simple stones (GoR C) Consider prolongation in complex stones (GoR C) Catheter related BU/UTI No available studies Defined as clean-contaminated – single dose Defined as clean-contaminated – single dose Defined as clean-contaminated – single dose Defined as clean-contaminated – single dose Defined as clean-contaminated – single dose Prolongation of ABP on individual basis Review studies contradictory Regimen not defined

4. Methods

5. Results per type of procedure

A systematic search was performed in Medline, Cochrane Library and EMBASE and using the keywords antibiotic prophylaxis, prophylaxis, antibiotics, urological surgery, urogenital surgery and the procedures one by one. Approximately 200 abstracts were identified of which over 100 were not directly related to the topic. Of the remaining 95 reports, a majority was related to transurethral resection of the prostate (TURP). As this procedure has been reviewed by other authors by means of systematic review [5] and covered more recently by two meta-analyses [6,7], the outcome was built on these works. Also urodynamic studies were critically reviewed [8] and the conclusions reported. For all other procedures, the articles were systematically reviewed and the conclusions compared to those drawn by one other recent systematic review by a group from the Netherlands [9] and the conclusions presented by a working group in the USA [10]. The quality of the studies was found to vary largely, essentially in terms of design, description of randomisation, sample size, level of dropout, power, and strength of the conclusion. The procedures were divided between diagnostic procedures (cystoscopy, urodynamic studies and transrectal core biopsy of the prostate) and therapeutic endoscopic procedures (transurethral resection of bladder tumours and of the prostate, endourological interventions including shock wave lithotripsy), open and laparoscopic interventions (nephrectomy, pelvic junction surgery, total prostatectomy, cystectomy with urinary diversion) and elective surgery for benign scrotal surgery. As far as possible, the expected natural history of infectious rates is presented followed by the results of randomized placebo/no antibiotic controlled studies (RCT). Thereafter, RCTs of different antibiotic regimens are presented to detect the most rational one (shortest, low cost and effective course) when applicable. The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using ICUD standards (for details see Preface) [11,12]. The LoE and GoR are given at the end of each surgical procedure and the recommendation reported to the summary table.

5.1. Cystoscopy The natural history of the events following cystoscopy is important. In one study from 1990, Clark and Higgs [13] showed the appearance of bacteriuria three days after instrumentation in 12/161 (7.5%). In two recent studies, a spontaneous acquired bacteriuria was observed in 2.7% and 4.5% [14,15]. The fate of this bacterial contamination is not known and the spontaneous cure is probably high. In a large British study with flexible cystoscopy [16], a single dose of trimethoprim or ciprofloxacin reduced by more than half, 2% and 3.2% respectively, the post-cystoscopy frequency of bacteriuria as compared to placebo (6.8%). These results were in accordance with an older study observing a significant reduction of post-cystoscopy bacteriuria and clinical UTI [17]. Other studies were contradictory in their results, some advocating antibiotic prophylaxis [18,19], others finding it no use [20–23]. The overall conclusions are that the frequency of bacteriuria is low and that of clinical infections even lower, and that the frequencies of these events are, globally, marginally reduced by antibiotic prophylaxis. Thus, the recommendation of giving systematically antibiotic prophylaxis to all patients undergoing cystoscopy cannot be advocated in view of the lack of knowledge of the risk associated with the bacterial contamination and its fate, the low frequency of clinical infection, the recommendation and praxis in most European countries, the enormous amount of such instrumentation and overtreatment, and the subsequent amount of antibiotics that would be used (LoE 1b–2b, GoR A). 5.2. Urodynamic studies Most studies are carried out on women investigated for incontinence. In a meta-analysis of 995 patients including eight RCT, bacteriuria (>105 CFU/ml) was reduced by 40% by antibiotic prophylaxis [8]. The authors concluded that it was necessary to treat 13 individuals in order to avoid one episode of bacteriuria. In one other study combining cystoscopy and urodynamic study in women,

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there was found to be no difference between one day of antibiotic prophylaxis and no antibiotics [24]. In one Swedish study of 123 consecutive men undergoing a flow-pressure investigation, 4.1% acquired bacteriuria and 2.5% fever [25]. The overall interpretation is, as for cystoscopy, that the frequency of infectious events is low, that the outcome and role of bacteriuria after urodynamic investigation is unknown and that there is a lack of support in the literature for the systematic use of antibiotic prophylaxis in patients without risk factors. For investigations of patients with other underlying urological diseases such as neurological bladder dysfunction, refer to the chapter on “UTI in patients with underlying urological diseases” (LoE 1a, GoR A). 5.3. Transrectal core prostate biopsy There are only very few studies on the natural history of infectious complications after transrectal prostate biopsy. In a few cohort series, infectious complications such as febrile UTI, acute prostatitis and sepsis are reported in frequencies between 2.9 and 10% [26–28]. In RCT, frequencies of 5–26% bacteriuria and up to 10% febrile UTI are given in the control groups [29–31]. In older studies, frequencies up to 48% have been reported [32,33]. There is a consistent significant reduction of the frequencies of both bacteriuria and febrile urogenital infections by antibiotic prophylaxis, below 5% in low-risk patients [29–34]. Recent studies have shown that one day [35,36] and even one single dose [31,37,38] is appropriate to keep the infectious rate at 1% or below, including less than 0.5% of sepsis. These low frequencies are confirmed by a few consecutive cohort series with antibiotic prophylaxis [39,40]. The antibiotic dose can be given in direct conjunction with instrumentation and there is now evidence for giving the medication 1–2 h before the procedure [37]. Fluoroquinolones achieve the highest concentrations in the prostate [41] and are best documented for prophylaxis. However, new studies have to be done to avoid the overuse of fluoroquinolones wherever possible due to the worldwide development of resistant strains in both community and hospital settings. It is unknown how long prophylaxis should be given to risk patients (risk factors are presented in the preceding chapter). It is also unknown whether spontaneous acquired bacteriuria after core prostate biopsy can spontaneously cure (LoE 1b, GoR A). 5.4. Transurethral resection of bladder tumour (TURB) Although TURB is one of the most frequent urological procedures, there are no base-line data. Only three older, rather weak, small-size studies covering antibiotic prophylaxis were disclosed [18,42,43]. The data from the studies do not give any evidence in favour of antibiotic prophylaxis in TURB. However, the studies focus only on smaller tumours or fulguration, an intervention very similar to standard cystoscopy, and do not mirror the large spectrum of resection of bladder cancer from the single minor non-muscle-invasive bladder tumours (Ta, G1–2) to large muscleinvasive (T2, G3), sometimes necrotic, tumours that are part of daily practice. Future studies covering all TURB procedures and breaking them down according to the intervention’s level of severity and difficulty, duration and other risk factors has to be undertaken (LoE 2b, GoR C). 5.5. Transurethral resection of the prostate (TURP) TURP is the most well studied of all urological studies. More than 50 studies have been conducted, some of them of medium to high quality. Postoperative bacteriuria has been reported in up to 70% of the patients. In a systematic review of subsequent studies from the 1980s, it was shown that antibiotic prophylaxis reduced

the frequency of bacteriuria in men with pre-operative sterile urine from an average of 34% to 10% [5]. In recent years, two high-quality meta-analyses have been done including 32 and 28 participantcontrolled studies (respectively [6,7]). The conclusions are similar: a short course of antimicrobial agents reduces the risk of bacteriuria from an average of 26% to 9%. Berry and Barrat also analysed the impact on sepsis: the impact was even more important, reducing the risk from 4.4% to less than 1%. Both reviews show that a prolonged course (<72 h) is more effective than a single dose, but less effective than one week [6]. Any antibiotic except nitrofurantoin would do. In a recent high-quality multicentre study conducted in Germany, Wagenlehner et al. [44] confirmed these results, although the difference was less marked. Interestingly, they also showed that the total amount of antibiotics used in the study was lower in the antibiotic prophylaxis group, confirming data from one older similar analysis [45]. This observation is interesting in the argument for antibiotic prophylaxis, as nowadays there is a high level of concern about the total amount of antibiotics used in the community. Long operation time, postoperative disconnection of drainage system and longer catheterisation period were associated with increased frequency of bacteriuria despite antibiotic prophylaxis [46] (LoE 1a, GoR A). Consequently, there is a scientifically high level of evidence for the use of short regimens of antibiotic prophylaxis in TURP to reduce the postoperative frequencies of both bacteriuria and, especially, severe febrile infections and sepsis. The conclusions are not applicable to other prostate interventions such as adenoma enucleation, micro-wave thermotherapy or laser ablation, as there are no quality RCT studies on these matters. 5.6. Extracorporeal shock-wave lithotripsy (ESWL) A remarkably poor number of studies have been conducted for such an enormous worldwide procedure. In a few follow-up studies, the frequency of post-ESWL bacteriuria has been shown to be ≤5% in patients without known risk factors [47–49]. In only one [50] of five randomized placebo/non-antibiotic-controlled studies was a significant reduction demonstrated [50–54]. In most studies, the sample size or the frequencies of infections were low and no clear-cut conclusions could be drawn. In a systematic review and meta-analysis Pearle analysed eight prospective controlled studies [55]. The frequencies of bacteriuria and/or symptomatic UTI were reported to be 0–28% in the non-antibiotic control group and 0–7% in the intervention group. They estimated the risk of acquiring a UTI to be 5.7% and 2.1%, respectively. The overall conclusion is that in patients with sterile urine, uncomplicated kidney or ureteral stones and no known risk factors, the risk of post-ESWL bacteriuria/UTI is low, that the reduction by antibiotic prophylaxis is marginal and that, subsequently, there is no evidence for antibiotic prophylaxis in this category of low-risk patients, which represents the majority of patients undergoing ESWL (LoE 1a–2b, GoR A). 5.7. Ureteroscopy (URS) No studies on ureteroscopy as a diagnostic tool were found. Two studies concerned with stone management were identified [56,57]. Both show a reduction of bacteriuria but not of symptomatic UTI. One study comparing ESWL and URS for mid and distal ureteral stones demonstrated a higher frequency of complications including infectious complications in the URS-treated group as compared to the ESWL group [58]. The studies do not differentiate the degree of invasiveness in terms of stone burden and localisation (impacted proximal stone versus small mid and lower stones), surgical difficulty and complexity of the treatment, duration of operation, experience of the surgeon; a weakness, as it is known that the

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risk of infectious complications varies [59]. In conclusion, there is only a weak level of evidence for antibiotic prophylaxis in URS, although it is probably of value, especially in complex stone situations (diagnostic: LoE 2b, GoR C; stone management: LoE 2b, GoR B).

5.8. Percutaneous stone extraction (PCNL) Bacteriuria is reported in up to 35% and febrile UTI in around 10% of patients receiving no antibiotics [60,61]. Only one controlled study comparing antibiotic prophylaxis with no antibiotics was identified [56] and one comparing two different antibiotic regimens [62]. As for complicated URS, the danger of PCNL in terms of severe, febrile UTI and sepsis has been underlined [59,63]. Antibiotic prophylaxis appears to reduce the frequencies of infectious complications and there seems to be no difference between antibiotics. As mid-stream urine culture is not a good predictor for the endogenous presence of pathogens [63], the urologist faces an incertitude as to the real risk of infectious complications. Moreover, following the remarkable improvement of equipment, older studies are not necessarily representative of the present profile of renal stone management. Consequently, as for URS, there is a substantial lack of data on the use of antibiotics in PCNL and only very limited evidence for antibiotic prophylaxis. Nonetheless, the infectious rates being high and the potential complications severe, there are reasons to believe that antibiotic prophylaxis is of value. Large multicentre controlled studies focusing on antibiotic regimens and risk factor analysis are required (LoE 2b, GoR B).

5.9. Open and laparoscopic urologic surgery An extensive search on open and laparoscopic surgery, nephrectomy, nephron-sparing surgery, pelvic junction reconstruction bladder resection, cystectomy, total/radical prostatectomy and scrotal surgery has revealed the lack of RCT and the weaknesses of available data [9,10]. Expected data have to be extrapolated from bottom-line data on type of surgery [3] and from colorectal and abdominal gynaecologic surgery. There are indications that infectious complications are fewer after laparoscopic and robotic surgery in abdominal surgery [64]. The issue has however not been studied in RCT as far as urologic surgery is concerned. A few examples of common surgery by type of intervention follow.

5.9.1. Clean operations Trans-abdominal open or laparoscopic nephrectomy is classed as a clean operation. Only one RCT was identified [65]. Infectious complications in terms of wound infection were 20.4% when no antibiotics were given versus 0% for patients receiving one single preoperative dose. The results indicate a marked impact of antibiotic prophylaxis but no other study confirms the data. In one report on surgical site infections (SSI) in which antibiotic prophylaxis was not in the protocol, Montgomery reports wound infections in 6.8% (range 5.0–7.9%) in clean and clean-contaminated hand-assisted kidney surgery, with no difference whether the urinary tract was opened or not [66]. In one study of clean surgery in patients with or without a risk factor for SSI, antibiotic prophylaxis had no impact in low-risk patients whereas it reduced the frequency in patients with at least one risk factor [67]. Scrotal surgery for elective benign conditions, mainly hydrocele and spermatocele, is a reasonably clean procedure. No RCT was identified. In a few recent studies [68,69], including a Medline search review, infectious complications were reported in up to 9%. In most reports, no antibiotic prophylaxis had been used. A lower frequency of infections (3.6%) was observed in patients

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receiving antibiotic prophylaxis [70]. Multicentre RCT have yet to be undertaken to confirm this finding (LoE 3, GoR C). 5.9.2. Clean-contaminated operations Nephroureterectomy, kidney resection and pelvic junction surgery have, to the best of our knowledge, never been studied in RCT. The searches have revealed no RCT on antibiotic prophylaxis versus placebo/no antibiotic in total prostatectomy. Thus, there is a lack of baseline data on the infectious profile of this nowadays so frequent operation. There are a few retrospective and prospective cohort studies looking at SSI and catheter-associated bacteriuria following different antibiotic regimens. The conclusion of this series of publications is that the frequency of wound infections is low and that a single oral antibiotic dose is sufficient [70–73]. The importance of the post-operative catheter-associated bacteriuria, observed in the majority of the patients at catheter removal, is unknown as is whether it has to be treated or not (LoE 3, GoR B). There are no RCT on antibiotic prophylaxis in urologic surgery including urine deviation and the use of bowel. Postoperative wound infection is reported in up to one-third of cases, usually 10–15%, even when using antibiotic prophylaxis [74–76]. Also UTI, pyelonephritis and sepsis are added to the burden of infections. 5.9.3. Penile prosthesis Implantation of penile prosthetic devices is a special case. Infection of the prosthetic device remains the most troublesome complication. Infection may lead to more surgery, loss of penile tissue and even the inability to replace penile prosthesis. Antibiotic prophylaxis in addition to standard sterility and good surgical technique reduces the risk of infection [77,78]. 6. Discussion The present review requires a certain number of remarks on the validity and relevance of the references revealed by an in-depth search of the literature. Firstly, the remarkable technical development and medical achievements in urology during the past 25–30 years mean that older studies from the 1970s and 1980s have partly lost their relevance. Secondly, the quality of older studies in the present view of good clinical practice is usually poor in terms of sample size, consistency in definitions, statistical estimates and power. Thirdly, risk factors for infectious complications are rarely debated and, as shown in the preceding section about preparation of the patient for surgery, our knowledge of the relative importance of individual risk factors and their cumulative impact is limited. Fourthly, numerous reports have given results on a mixture of procedures and the breakdown has shown so low a sample size per procedure that it is difficult to draw a conclusion. Fifthly, the lack of consistency in definitions of infectious complications, especially UTI, the level of bacterial growth and the relation between clinical symptoms and bacterial growth weakens the possibility of comparison. Clear definitions are often lacking. The results are therefore more indicative, than proof. Against this background, large cohort studies and historical controls gain indicative importance by giving a “natural history” of the events after a defined intervention and therefore have also been used to some extent. It is remarkable that there are so few studies on very frequent interventions such as transurethral resection of bladder tumours and endoscopic stone management including ESWL. It is thus not astonishing that Bootsma et al. stated that “except for TURP and prostate biopsy, there is a lack of well performed studies investigating the need for antibiotic prophylaxis in urologic interventions”. On the other hand, urologists need a working hypothesis for antibiotic prophylaxis.

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One approach is to stick to the classification of surgical interventions in clean, clean-contaminated and contaminated classes and follow the experience of other surgical practices such as general, orthopaedic and gynaecologic surgery. Theoretically, there should be no need for antibiotic prophylaxis in clean operations, whilst a single dose should be advocated for clean-contaminated procedures. In case of contaminated procedures (i.e. urine deviation with bowel, presence of asymptomatic bacteriuria in urine), the antibiotic regimen’s start and length is less obvious and documentation is insufficient. In standard colorectal surgery, usually a single dose or very short regimen is advocated. Bacteriuria is a known risk factor and, in conjunction with urological procedures should therefore, reasonably, be treated. Thus, individual adjustment has to be suggested depending on patient susceptibility, bacterial load and the development of the procedure in terms of spillage and duration. However this approach is not totally satisfactory; it is only indicative and usually no strong recommendations can be given in guidelines, such as those of the European Association of Urology, except in a few situations [79]. Therefore, there is an inevitable discrepancy between the level of evidence and the grade of recommendation in Table 1. The role of antibiotics is to reduce the bacterial burden, not necessarily to cover all potential strains. Also, antibiotics for prophylaxis should ideally be limited to a few and usually different from those used for therapeutics to avoid an overload of drug doses and local environmental pressure. Recommendations should be set in cooperation with specialists in infectious diseases and hospital environmental hygiene. 7. Further research This review underlines the absolute need for serious, wellconducted studies and large, multicentre quality registries per type of procedure including breakdowns in the level of severity of surgery and the reporting of potential risk factors. 8. Conclusions An extensive search of the literature and systemic reviews has revealed a lack of well-built data for antibiotic prophylaxis in urological surgery. Strong recommendations can only be given for transrectal core biopsy of the prostate and transurethral resection of the prostate. As surgery has markedly changed over the decades and because older studies vary so much in quality, it is mandatory to initiate new large industry-independent, prospective, randomised controlled studies and to set up large prospective quality registries and infectious control materials. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required. References [1] Chodak GW, Plaut ME. Systemic antibiotics for prophylaxis in urologic surgery: a critical review. J Urol 1979;121:695–9. [2] Grabe M. Controversies in antibiotic prophylaxis in urology. Int J Antimicrob Agents 2004;23(Suppl. 1):S17–23. [3] Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1999;20:250–78 [quiz 279–80]. [4] Bjerklund Johansen TE, Cek M, Naber K, Stratchounski L, Svendsen MV, Tenke P. Prevalence of hospital-acquired urinary tract infections in urology departments. Eur Urol 2007;51:1100–11 [discussion 1112]. [5] Grabe M. Antimicrobial agents in transurethral prostatic resection. J Urol 1987;138:245–52. [6] Berry A, Barratt A. Prophylactic antibiotic use in transurethral prostatic resection: a meta-analysis. J Urol 2002;167(Pt 1):571–7.

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