4 Manish N. Patel & Jorge Gutierrez‐Aceves Wake Forest University School of Medicine, Department of Urology, Winston‐Salem, NC, USA Sepsis from a urinary source is one of the most feared complications in urologic practice due to its potential for increased morbidity and mortality after urologic surgery. In this chapter, we will discuss the importance of appropriate preoperative workup, use of adequate antibiotic prophylaxis, as well as intraoperative and postoperative measures to help prevent the development of adverse events related to infection and sepsis. According to the European Section for Infection in Urology, the prevalence of hospital‐acquired infections varies between 3.5 and 9%. The prevalence of hospital‐acquired urinary tract infections (HAUTI) was found to be 9.4% over an 8‐year period between 2003 and 2010. The most common presentation was asymptomatic bacteriuria in 27%, followed by cystitis in 26%, and pyelonephritis in 20%. Some 10.3% of all cases presented as urosepsis [1]. Among those patients with nosocomial urinary tract infections (UTIs), almost 80% had a prior history of urologic surgery; endourologic procedures had been undergone in 50%, open or laparoscopic surgery in 45%, and prostate biopsies in 5% [2]. These data suggest that preventive measures, such as a strict preoperative evaluation and correct antibiotic prophylaxis in surgical patients, must be improved. The prophylactic use of antibiotics can reduce the risk of surgically related infection. The European Association of Urology (EAU) and American Urological Association (AUA) have both published guidelines for best practice in antibiotic prophylaxis in urologic surgery. The AUA most recently updated their guidelines in 2009 and the EAU in 2014 [3, 4]. These guidelines are extremely helpful to standardize the administration of antibiotics prior to surgery. However, local practice should be based on or adjusted according to local or even hospital microbiologic patterns and requirements, so it is crucial that each center and department reviews regularly its infection patterns and antibiotic resistance. There is currently no uniformly accepted definition in the literature to delineate infection versus sepsis, which may account for the wide range of incidences reported [5]. After any diagnostic or therapeutic urologic procedure, UTIs can be present as a simple bacteriuria with limited clinical symptoms or they can result in severe sepsis or even septic shock. It is difficult to predict in which patient a serious complication will develop, but several publications describe potential risk factors that can contribute to this scenario. It is crucial to recognize patients at risk of complications with a complete preoperative evaluation to establish a prompt diagnosis and proper treatment in the event of a postoperative infectious complication. Classically, urosepsis is defined as a sepsis caused by UTI; this occurs in 7–25% of all septic cases [6]. An infectious complication is triggered during urologic surgery when urinary bacteria and their products enter the bloodstream via a vascular, lymphatic, or urothelial disruption. Manipulation of infected urine or infection stones with an increase in pressure mainly in the collecting system causes an intense liberation of bacteria and endotoxins via direct absorption, pyelovenous–lymphatic or pyelotubular backflow, and forniceal rupture, triggering a systemic inflammatory response [7]. There is a neurohumoral generalized pro‐ and anti‐inflammatory response. This begins with cellular activation of monocytes, macrophages, and neutrophils that interact with endothelial cells through numerous pathogen‐recognition receptors [8]. A further host response includes the mobilization of plasma substances, such as tumor necrosis factor (TNF), interleukins (ILs), caspases, proteases, leukotrienes, kinins, reactive oxygen species, nitric oxide, arachidonic acid, platelet activating factor, and eicosanoids. TNF‐α and IL‐1 are the most important proinflammatory cytokines and exhibit similar biologic properties. They influence the temperature regulatory centers in the hypothalamus, resulting in fever. They also have an effect on the formation reticularis in the brainstem, which renders the patient somnolent and comatose. Release of corticotropin in the pituitary gland is increased, which stimulates the adrenal gland. These factors also stimulate hematopoietic growth factors, which leads to the formation of new neutrophils and the release of stored ones. The neutrophils are additionally activated and produce bactericidal substances, such as proteases and oxygen radicals. B and T lymphocytes are stimulated for the synthesis of antibodies and cellular immune reaction. In the continuing septic process, however, apoptosis of B cells, CD4 helper cells, and follicular dendritic cells causes an anti‐inflammatory immune suppression, called transient immune paralysis [9]. Activation of the complement and coagulation cascades further amplifies this chain of events. There is microvascular injury, thrombosis, and loss of endothelial integrity (capillary leak), resulting in tissue ischemia. This diffuse endothelial disruption is responsible for the multiple organ dysfunction and global tissue hypoxia that accompany severe sepsis/septic shock [10]. The pathogens associated with UTIs and urosepsis have not varied greatly over the last decades and concern centers around the considerable changes in resistance patterns [1]. A continuous assessment of local patterns is important to establish the most appropriate antibiotic regimens to prevent infectious complications most efficaciously. Escherichia coli remains the single most common microorganism to cause urinary infection. This is followed by Klebsiella and Pseudomonas, frequently associated with stone disease. Furthermore, the increasing presence of Gram‐positive bacteria such as Enterococcus and Staphylococcus should be noted [1]. DasGupta et al. reported that 40% of urology inpatients had Gram‐positive organisms, with Enterococcus accounting for 27% [11]. Several reports have shown that other organisms have increased not only their incidence, but also their resistance to antibiotics commonly used in urology, including trimethoprim, quinolones, cephalosporins, and aminoglucosides, such as gentamicin; this is the case for Pseudomonas aeruginosa, methicillin‐resistant Staphylococcus aureus [12], Serratia spp., and Clostridium difficile. Many common antibiotics once prescribed for uncomplicated urinary infection such as ciprofloxacin and trimethoprim now have high resistance rates. The rates of resistance from 2000 to 2008 to ciprofloxacin rose in Germany (2 to 21%), Spain (15 to 31%), Sweden (0 to 7%), and the UK (1 to 15%), as well as to trimethoprim in Germany (23 to 37%), Spain (25 to 37%), Sweden (9 to 17%), and the UK (13 to 46%) [13]. This rise in resistance of urinary pathogens towards quinolones has been reported worldwide and might be the consequence of its overuse due to its efficacy in treating other infections and uncomplicated UTIs, as well as its misuse as prophylaxis in some urologic diagnostic procedures. In cases of urosepsis, resistance to commonly prescribed antibiotics was high and rates ranged from 8% (imipenem) to 62% (aminopenicillin/β‐lactamase inhibitors); 45% of Enterobacteriaceae and 21% of P. aeruginosa were multidrug‐resistant [14]. In recent years, the incidence of sepsis has increased, but the associated mortality has decreased, suggesting improved management of patients [15]. Besides correct management, the role of prevention is of great importance and it is imperative to identify preoperative risk factors, apply adequate prophylaxis, and try to minimize intraoperative risks, in order to reduce the incidence of septic episodes or allow early recognition of the features that can lead to one. The EAU in its Guidelines on Urological Infections recommends the following basic preventive measures of proven efficacy in any urologic patient undergoing surgery [4]: All patients who are being considered for genitourinary surgery should be evaluated with a complete medical history, physical examination, and laboratory tests, including an obligatory urine culture; this will identify those patients with a high risk for development of an infectious complication [16]. There are well‐recognized risk factors that for academic purposes can be categorized under the following headings (Table 4.1). Table 4.1 Risk factors associated with postoperative infectious complications in genitourinary surgery. There are several patient characteristics known to increase the risk of infectious complication after surgery. These include patients who are immunosuppressed secondary to diverse causes, among others; those with malignant or autoimmune diseases receiving chemotherapy or chronic use of corticosteroids usually have impaired infection resistance. Also patients of advanced age or poor nutritional status, with diabetes, obesity, significant kidney or liver diseases, and female patients have a higher risk [6]. Other related factors are the presence of a coexistent infection at another site at the time of surgery or prolonged hospitalization. Urinary diseases or their management increase the possibility of colonization and chronic bacteriuria. Risk factors in urologic patients are anatomic anomalies, voiding dysfunction, urinary diversion, active UTI, obstruction of the urinary tract, stone disease, indwelling catheters, and endogenous material, such as ureteral stents and nephrostomy tubes. Many of these patients will have a positive urine culture and must receive preoperative antibiotics appropriately tailored to culture‐specific organisms; at the end of treatment urinary evaluation must be repeated. Rao et al. reported that bacteriuria and pyuria are risk factors for bacteremia; they also found that preoperative bacteriuria had a positive predictive value (PPV) of 0.53 for detection of endotoxemia, another important risk factor for the development of urosepsis [17]. Any procedure performed in patients with urolithiasis has a potential risk for postoperative infection due to bacterial colonization of the urinary tract, infection stones, or urinary drainage obstruction and indwelling catheters. Prolonged surgical time, high intrapelvic pressures during endourologic procedures, such as percutaneous or retrograde renal surgeries, and bleeding during procedure carry a high risk of postoperative infection. Open or laparoscopic surgeries, which involve the gastrointestinal or genital tract, such as urinary diversions or vesicovaginal fistula repair, also should be considered high‐risk procedures for infection. These factors frequently act in an additive manner, compounding their impact. The likelihood of bacterial invasion is also affected by the amount of bacteria at the site of the surgical procedure. All procedures invading the urinary tract are considered “clean–contaminated.” The likelihood of bacterial invasion is increased if bacteriuria is present or adequate wound preparation and surgical techniques are not employed [9]. Prophylaxis means a brief course of antibiotics administered before or at the start of an intervention, and is used to minimize the infectious complications resulting from diagnostic and therapeutic interventions. While the rationale for the use of antibiotics is well accepted, possible side effects and development of antimicrobial resistance patterns are potential risks. Therefore, an antibiotic prophylaxis policy should be well considered and based on high levels of evidence [18]. Surgical antimicrobial prophylaxis is recommended only when the potential benefit exceeds the risks and anticipated costs; it has been demonstrated in a variety of settings that surgical antimicrobial prophylaxis, by reducing the incidence of surgical site infections, reduces costs. Conversely, excess and/or inappropriate antimicrobial prophylaxis increases costs, which is reversed by measures to improve compliance with evidence‐based recommendations [19]. A multicenter study looked a the rate of antibiotic resistance, daily antibiotic dose, and cost after implementation of antibiotic guidelines. The rate of resistance of E. coli to piperacillin/tazobactam (9.1 vs. 5.4%), gentamicin (18.3 vs. 11.2%), and ciprofloxacin (32.3 vs. 19.1%) decreased significantly after guideline introduction. The defined daily dose (DDD) use of ciprofloxacin fell from 4.2 to 0.2 DDD per 100 patient days after implementation, and antibiotic drug costs (€76 980 vs. €36 700) and costs related to postoperative infections (€45 870 vs. €29 560) decreased following introduction of the guideline [20]. In considering prophylactic treatment, the surgical site and the properties of the antimicrobial agent should be taken into account. The agent should achieve serum and tissue levels that exceed the minimum inhibitory concentration for organisms characteristic of the operative site. Furthermore, the optimal agent should have a long half‐life so as to maintain sufficient serum and tissue concentrations for the duration of the procedure without the need for redosing. It should be safe, inexpensive, and unlikely to promote bacterial resistance [3]. For prophylactic antimicrobial administration to be optimally effective, timing and dosing are critical. Infusion of the first dose should begin within 60 minutes of the surgical incision (with the exception of 120 minutes for intravenous fluoroquinolones and vancomycin). Correct dosing is equally important. Some drugs should be adjusted to the patient’s body weight. Oral administration is as effective as the intravenous route for antibiotics with sufficient bioavailability. This is recommended for most interventions, when the patient can easily take the drug between 1 and 2 hours before intervention. Additional doses are required intraoperatively if the procedure extends beyond two half‐lives of the initial dose [21]. With few exceptions, the published literature suggests that antimicrobial prophylaxis is unnecessary after wound closure or upon termination of an endoscopic procedure; in most cases, antimicrobials should be given in a single dose, or at least discontinued within 24 hours of the end of the procedure [22]. Three circumstances in which a longer duration of antimicrobials is frequently considered include the placement of prosthetic material, the presence of an existing infection, and the manipulation of an indwelling tube [23]. In cases where an existing infection is present, a therapeutic course of antimicrobials should be administered in an attempt to sterilize the field. In the absence of pre‐existing bacterial colonization, there is no evidence that prophylaxis should extend beyond 24 hours following a procedure. In cases where prolonged catheterization follows the procedure (e.g. radical prostatectomy), antimicrobial therapy at the time of catheter removal may be therapeutic rather than prophylactic, since colonization has likely occurred. An alternative is to culture the urine 24–48 hours prior to the intended catheter removal, and administer culture‐directed therapy. This is not practical in cases of catheterization for only 48–72 hours. An option then is to administer antimicrobial treatment empirically [3]. The use of preoperative antibiotics can reduce the risk of surgically related infection. Table 4.2 summarizes the recommendations for best practice in antibiotic prophylaxis in urologic surgery from the published EAU and AUA guidelines [3, 4]. Table 4.2 Recommended antimicrobial prophylaxis in genitourinary surgery and procedures. Data from [3, 4]. TURP, transurethral resection of prostate; TURBT, transurethral resection of bladder tumor; TMP–SMX, trimethoprim–sulfamethoxazole; BLI, β‐lactamase inhibitor. UTIs and other infectious complications can be present in 1–26% of patients treated with transurethral resection of prostate (TURP). Risk factors associated with postoperative bacteriuria are operative time, disconnection of the closed urine drainage system, prolonged postoperative catheterization (≥3 days), and preoperative catheterization (within 1 month prior to surgery) [24, 25]. TURP is the most studied procedure regarding the use of antibiotic prophylaxis. Two large meta‐analyses have been published which include 38 and 32 randomized clinical trials respectively, and both concluded that the benefit obtained from antibiotic prophylaxis in TURP is sufficiently well demonstrated [26, 27]. The incidence of bacteriuria is reduced (26 to 9%), as is that for clinical sepsis (4.4 to 0.7%). Wagenlehner et al., in a large, prospective multicenter study, compared two antibiotics regimens with a control group; they found that the patients receiving antibiotics showed lower levels of bacteriuria compared with controls and demonstrated that the presence of bacteriuria post TURP (CFU >104/ml) is a risk factor for infectious complications [28]. There was no statistical difference between antibiotic regimens. Bacteriuria is not considered to be an infectious complication but the last study showed that there is a correlation between bacteriuria and the development of infectious complications. The AUA guidelines recommend the use of antimicrobial prophylaxis in all patients. The suggested antimicrobial prophylaxis is fluoroquinolone or trimethoprim–sulfamethoxazole as antimicrobial of first choice, and alternatively a first‐ or second‐generation cephalosporin, aminoglycosides ± ampicillin or amoxicillin/clavulanate, before the start of TURP and until less than 24 hours postoperatively [3]. The EAU guidelines recommend a very similar antibiotic regimen in all patients other than those at low risk or with a small prostate [4] (Box 4.1). The AUA guidelines recommend the same regimen of antimicrobial prophylaxis mentioned above for TURP in all patients undergoing transurethral resection of bladder tumor (TURBT). In contrast, the EAU guidelines recommend that antimicrobial prophylaxis for TURBT is unnecessary unless the patient has some risk factors for infectious complications, or a large tumor requiring a prolonged resection time, or a necrotic tumor. Scientific evidence supports the recommendation by the EAU in two studies that did not show any difference between antibiotics and placebo in terms of reduction of the rate of bacteriuria [29, 30]. Yokoyama et al., in a prospective, randomized study in patients with no risk factors for complications, corroborated these findings; no differences were found in terms of infectious complications between groups given antibiotics or placebo. The authors concluded that antibiotics might be deferred and only given to patients who develop postoperative infections [31]. In contrast to this, a retrospective review of patients undergoing TURBT looked at factors that lead to unplanned hospital readmission rates. On multivariable analysis, the use of preoperative antibiotics was found to be significant [32]. This finding is likely related to development of hematuria related to UTI but was not specifically elucidated. There is little evidence for any benefit of antibiotic prophylaxis in TURBT. However, antibiotic prophylaxis should be considered in patients with large tumors with a prolonged resection time, and those with risk factors for infection [30, 33, 34]. Other transurethral procedures involving manipulation, like bladder biopsy, laser prostatectomy, and internal uretrotomy, may be similar in terms of tissue trauma, and the AUA guidelines suggest that data regarding TURP and TURBT could be extrapolated to these procedures. Although infection or sepsis may occur despite a sterile preprocedure urine culture, every effort should be made to sterilize the urinary tract before instrumentation. Preoperative treatment with culture‐specific antibiotics and subsequent documentation of successful treatment is imperative. While having a negative preoperative urine culture is desirable for all endourologic procedures, this is not always possible, mainly because of stone or urinary tract colonization. In these cases, oral culture specific antibiotic therapy should start at least 1 week before the planned procedure or intravenous therapy at least 24 hours prior to the planned procedure. Patient‐related risk factors associated with the development of postoperative infections include: Whereas urinary tract‐related risk factors include: The use of prophylactic antimicrobial treatment in patients who undergo shock‐wave lithotripsy (SWL) is debated in the literature. The AUA Best Practice Policy guidelines on antibiotic prophylaxis recommends preoperative antibiotic prophylaxis for all patients undergoing SWL [3]. This recommendation was based on a 1997 meta‐analysis by Pearle and Roehrborn [35] combining data from eight randomized controlled trials. This study found that the post‐SWL urinary tract infection rate for the placebo/no‐prophylaxis patients was 5.7% (range, 0–28%) compared to 2.1% (range, 0–7.7%) for patients who were given preprocedural prophylaxis. The relative risk of UTI with prophylaxis was 0.45 (P = 0.0005). The EAU based their contemporaneous recommendations [4] on a narrower list of randomized control trials that focused on the effects on antibiotic prophylaxis rather than the treatment itself. Along with follow‐up studies they found that the rates of post‐SWL symptomatic UTI and asymptomatic bacteriuria were low both with and without prophylaxis [18]. Their ultimate recommendation is against antibiotic prophylaxis prior to SWL in patients without stents or positive urine cultures. Since the time of the original AUA guideline statement, Lu and colleagues re‐examined the available data in their own meta‐analysis including nine randomized trials (1364 patients) [36]. Lu showed that antibiotic prophylaxis did not significantly reduce the risk of fever (relative risk [RR] = 0.36, P = 0.31) or overall asymptomatic bacteriuria (RR = 0.77, P = 0.17). There was a trend toward protection against UTI (RR = 0.54, P = 0.05); however, there was no difference in UTI rates for patients with preoperative ureteral stents (RR = 0.85, P = 0.75). Duvdevani et al. has supported the recommendation that antibiotics prophylaxis is only indicated in patients with risk factors such as those listed in Table 4.1 or those undergoing a concomitant urologic procedure at the time of the SWL [37]. Although the rate of bacteremia post‐SWL is reported to be as high as 14%, the rate of sepsis is less than 1%, and the use of prophylaxis remains controversial [38]. The key points in prevention are listed in Box 4.2.
Preoperative Antibiotics and Prevention of Sepsis in Urologic Endoscopic Surgery
Introduction
Pathogenesis of urosepsis
Bacteriology of urinary infections and sepsis
General measures of sepsis prevention in genitourinary surgical patients
Preoperative evaluation
Risk factors for infectious complication
Related to patient
Related to urinary tract diseases
Related to procedure
Immunosuppression
Malignancy
Autoimmune diseases
Chronic corticosteroid use
Diabetes mellitus
Poor nutritional status
Severe kidney or liver dysfunction
Advanced age
Female
Distant coexistent infection
Prolonged hospitalization
Chronic bacteriuria
Voiding dysfunction
Urinary diversion
Obstruction
Stone disease
Indwelling catheters
Endogenous material (ureteral stents)
Anatomic anomalies
Impaired urinary flow
Stone disease management
Incisional therapy
Surgery of long duration
Involvement of genital tract
Involvement of gastrointestinal tract
Prosthesis
Related to the patient
Related to urinary tract diseases
Related to procedure
Antibiotic prophylaxis
Indication
Antibiotic scheme
Procedure
AUA
EAU
First choice
Alternative
Duration
Remarks
Diagnostic procedures
Cystography, cystoscopy, ureteroscopy, urodynamics
If risk factors
If risk factors
Fluoroquinolone or 2nd‐generation cephalosporin or TMP–SMX
Aminoglycoside ± ampicillin or amoxicillin/clavulanate
≤24 hours
If urine culture is negative, antimicrobial prophylaxis is not necessary
Prostate biopsy
All
All
Fluoroquinolone or TMP–SMX
Aminoglycoside + metronidazole or clindamycin
≤72 hours
Endourologic surgery and shock‐wave lithotripsy
Shock‐wave lithotripsy
All
If risk factors
Fluoroquinolone or TMP–SMX or 2nd/3rd‐generation cephalosporin
Aminoglycoside ± ampicillin or amoxicillin/clavulanate
≤24 hours
Patients with ureteral stent, nephrostomy obstruction and infection stone
TURP/TURBT
All
If risk factors
Fluoroquinolone or TMP–SMX or 2nd/3rd‐generation cephalosporin or aminopenicillin/BLI
Aminoglycoside + ampicillin or 1st‐generation cephalosporin or amoxicillin/clavulanate
≤24 hours
Consider in large necrotic tumors
Ureteroscopy
All
If risk factors
2nd/3rd‐generation cephalosporin or TMP–SMX or aminopenicillin/BLI or fluoroquinolone
Aminoglycoside ± ampicillin or 1st‐generation cephalosporin or amoxicillin/clavulanate
≤24 hours
Percutaneous renal surgery
All
All
2nd/3rd‐generation cephalosporin or TMP–SMX or aminopenicillin/BLI
Ampicillin/sulbactam or fluoroquinolone or 1st‐generation cephalosporin
≤24 hours
Length of short course to be determined, intravenous route suggested
Open or laparoscopic surgery
Clean operations
If risk factor
All
1st‐generation cephalosporin
Clindamycin
Single dose
Consider in high‐risk and short postoperative catheter treatment
Clean–contaminated opening of urinary tract
All
All
2nd/3rd‐generation cephalosporin or aminoglycoside + metronidazole or aminopenicillin/BLI
Ampicillin/sulbactam
Fluoroquinolone
Single perioperative dose
Contaminated (involving bowel)
All
All
2nd/3rd‐generation cephalosporin or aminoglycoside + metronidazole or clindamycin
Ampicillin/sulbactam Ticarcillin/clavulanate Pipercillin/tazobactam Fluoroquinolone
≤24 hours
For surgery involving the colon, bowel preparation with oral neomycin plus either erythromycin base or metronidazole can be added
Implanted prosthetic devices
All
All
Aminoglycoside + 1st/2nd‐generation cephalosporin or vancomycin
Ampicillin/sulbactam Ticarcillin/clavulanate Pipercillin/tazobactam
≤24 hours
Preoperative antibiotics and preventive measures of sepsis in specific procedures
Transurethral surgery
Transurethral resection of prostate
Transurethral resection of bladder tumor
Other transurethral procedures
Management of nephrolithiasis
Shock‐wave lithotripsy
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