Brief Title: Antimicrobial Prophylaxis in Patients Who Underwent a Transurethral Resection of Bladder (TURB)

INTRODUCTION

• Org Study ID: URO-2995-19-20-1
• Secondary ID: N/A
• NCT ID: NCT04209192
• Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

BRIEF SUMMARY

Antimicrobial prophylaxis in urological procedures is aimed to reduce the risk of local and
systemic postoperative infections such as urinary tract infection or surgical site infection.
It should be recommended only when the potential benefit exceeds the anticipated risks and
costs. However, a wide variation in the use of periprocedural prophylactic antibiotics has
been demonstrated, which frequently is incurred as an inappropriate selection of
antimicrobials, inadequate schedule of administration or excessive duration of prophylaxis.

The increase in multidrug resistance of antibiotics in recent decades has been associated
with its misuse, resulting in an increased rate of morbidity and mortality, prolonged
hospital stays and increased care costs. Specifically, resistance to fluoroquinolones has
increased its prevalence, a group of antibiotics widely used in urology. Therefore, local
resistance patterns should be considered before following recommendations, especially in
populations with poor control of antimicrobial use.

Transurethral resection of bladder (TURB) has become a frequent surgical procedure, as it is
the main diagnostic and therapeutic tool for bladder cancer, representing the ninth most
common malignancy in the world. However, no recent randomized clinical trial has investigated
antimicrobial prophylaxis for TURB. It is well known that an expected complication of TURB is
urinary tract infection (UTI), which is the most common healthcare related infection
worldwide.

Under this premise, a randomized clinical trial is proposed to analyze the current panorama
of UTI as a transcendent postoperative complication of TURB, under the context of the new
emerging resistance parameters. The use of fosfomycin trometamol is proposed as a good
potential option for urological procedures due to its high activity against
multidrug-resistant gram-negative bacteria and its favorable pharmacokinetic parameters that
guarantees wide tissue penetration and a high urinary concentration, in a single dose, the
which will be compared with the control group with traditional prophylaxis (amikacin). The
relative risk of UTI will be estimated, as well as the attributable risk of the main risk
factors associated with this infection, allowing a better characterization of this population
for adequate decision making regarding this clinical challenge.

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DETAILED DESCRIPTION

In 1931, Stern and McCarthy created the first practical cut-out resectoscope, allowing
endoscopic diagnosis and treatment of bladder tumors for the first time in history. From now
on, TURB has been the cornerstone of the management of bladder tumors. Histological
evaluation is essential for the precise classification and staging of this cancer, as well as
the therapeutic modality of choice for most patients with bladder cancer

Epidemiology Bladder cancer is the most common malignancy of the urinary tract, being the
seventh most common cancer in men and number 17 in women. The worldwide incidence is 9 per
100,000 men and 2 per 100,000 women. More than 75,000 new cases of bladder cancer are
diagnosed in the United States of America annually, making bladder cancer the ninth most
common malignancy of the urinary tract. In addition, bladder cancer is responsible for 15,000
annual deaths in the United States of America, which makes it the thirteenth cause of death
in general and the second most common cause of death among genitourinary tumors

In Latin America, bladder cancer has an incidence of 5.6 per 100,000 inhabitants. Mexico
lacks reliable records of cancer epidemiology, however, in Mexico it corresponds to 14.4% of
genitourinary cancers, ranking as the fourth most frequent. Mortality in men is 3 per 100,000
and in women 1 per 100,000 with very high geographical variation due to unequal access to
health services. In a second level hospital in Mexico City were reported 861 cases of
genitourinary cancer, bladder cancer was accounted for 13%.

Urinary tract infection as a postoperative complication In urology, the act of
instrumentation is a potential contributor of infection risk.

Before finalizing the TURB, a urethral catheter is placed to irrigate and wash the bladder
three times with 100 mL of saline. At the end of the procedure, the bladder is completely
drained and the function of the catheter is guaranteed to assess a subsequent irrigation in
the postoperative period, for complications that may occur, such as haematuria or urinary
retention due to obstruction of a clot and / or irrigation of intravesical chemotherapy. In
the absence of complications, the catheter can be removed after 24 hours.

The risk of urinary tract infection is directly proportional to the duration of the
catheterization, measured in days (catheter days) and the surgical time. It is reported a
mean catheter day of 1.9 +/- 1.7 in 130 post-TURB patients. It is well known that urinary
tract infection (UTI) associated with catheter use is the most common healthcare related
infection in the world and is the result of widespread use of urinary catheterization. The
incidence reported of UTI in the literature after surgery is 5-10%. Antimicrobial prophylaxis
in TURB decreases the risk of UTI from 10.1% to 2.9%. In a series of 10,559 patients in the
United States of America the incidence of UTI in post-TURB patients was 3 to 5%, being the
most observed complication. The investigators concluded that as surgery time increased,
urinary tract infection increased (2.8% in 0-30min to 5.4% in> 90 min, P <0.001).

In addition, a patient with cancer is a host with increased susceptibility to acquire
infections. In the last 50 years the epidemiology of bacterial infections in cancer patients
has presented a continuous change influenced by the nature and intensity of chemotherapeutic
and immunosuppressive regimes and the widespread use of empirical and prophylactic
antibiotics

Antimicrobial prophylaxis in TURB Surgical antimicrobial prophylaxis is the systemic
administration of an antibiotic before, during and / or shortly after a urological procedure
aimed to reduce the risk of local and systemic postoperative infections, such as urinary
tract infection or surgical site infection. The optimal antimicrobial drug should be a
microbiologically active agent against the most frequent potential pathogens and must have
good pharmacological properties.

Antibiotics The antibiotics used for prophylaxis must be effective against the characteristic
bacterial microbiota of the surgical site and relevant to the disease. In addition, it must
be considered the properties of the antimicrobial agent, such as cost, convenience and
safety. It should reach tissue serum levels that exceed the minimum inhibitory concentration
for microorganisms characteristic of the surgical site, in this case Enterobacteriaceae and
Enterococci. Moreover, it must have a long half-life to maintain sufficient serum and tissue
concentrations throughout the procedure without the need to administer another dose. It must
be safe, cheap and unlikely to promote bacterial resistance.

For the urinary tract, cephalosporins, fluoroquinolones and aminoglycosides are generally
effective, have a long half-life, are cheap (when used as a single dose) and are rarely
associated with allergic reactions. In addition, fluoroquinolones and aminoglycosides can be
used in patients with a beta-lactam allergy. These antimicrobials can effectively cover the
expected organisms and meet the criteria indicated above.

Current recommendations and the context in Mexico The American Urological Association (AUA)
and the Japanese guidelines recommend the use of fluoroquinolones, trimethoprim-
sulfamethoxazole, penicillins, first or second generation cephalosporins or aminoglycosides
before the start of TURB as an antimicrobial prophylaxis. According to the guidelines of the
Canadian Urology Association (CUA), any randomized clinical trials of antimicrobial
prophylaxis in TURB were found, so the recommendations about antibiotic prophylaxis are based
on other endoscopic urological procedures. Use of fluoroquinolone are recommended for
prophylaxis before surgical procedure, also trimethoprim- sulfamethoxazole or third
generation cephalosporins can be used.

In a study of TURB in 2006, the investigators used oral levofloxacin 200mg as prophylactic
antibiotic, which was given 30-60 minutes before the procedure. However, in this context it
would not be convenient to use this regime, because in a study conducted in 2015 specified
that countries with poor control of the use of antimicrobials such as Mexico, there is a
trend towards bacterial resistance, placing fluoroquinolones as the second line of treatment
in urinary tract infection . An important cause of the emergence of these resistant strains
is the excessive use (treatment when it is not needed and prolonged exposure to therapy) of
antimicrobial agents for all indications.

Fluoroquinolone-based regimens, a pillar of prophylaxis guidelines, are increasingly
ineffective due to a constant increase in multidrug-resistant gram-negative bacteria (MDR).
The same concerns apply with second and third generation cephalosporins, which have
resistance problems and, if administered orally, do not have a good penetration in tissues
such as prostate.

Problem definition Since 2000 a serious global public health problem has arisen in relation
to the increase in antimicrobial resistance, particularly among the pathogens of the ESKAPE
group (Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter
species, Pseudomona aeruginosa and Enterobacteriaceae), which are microorganisms that cause
urinary tract infection. In addition to the increase in multidrug resistance to antibiotics
and their misuse, this has been associated with an increased rate of morbidity and mortality,
prolonged hospital stay and increased care costs.That's why antimicrobial prophylaxis is of
such magnitude and importance that it needs to be updated to its reasoned use in order to
improve its performance.

In the case of TURB, there is little evidence in the literature that recommends the use of
preoperative antimicrobial prophylaxis in TURB, due to the lack of studies on this subject.
The incidence of UTI in TURB has been reported between 2 to 39% and risk of infection in TURB
from 18 to 75%.

Justification Nosocomial infection has been associated with an increased length of
postoperative stays, rate of hospital readmission and the outpatient use of antimicrobial
agents, which significantly increases the costs and use of medical resources.

Optimally, the specific prophylactic regimen should be supported by clinical trials evidence.
In many cases, randomized clinical trials are not available. Such lack of data does not
impede the adequacy of some antibiotic regimes based on the efficacy of the drugs, the cost,
safety and knowledge of the microbiota of the surgical site. When selecting the antimicrobial
for prophylaxis, the clinician should be aware of the different resistance patterns in the
local community. Specifically, resistance to fluoroquinolones, which has increased their
prevalence, therefore, should be considered due to the high use of these agents for
antimicrobial prophylaxis in urological surgery.

Regarding the premise, "surgical antimicrobial prophylaxis is recommended only when the
potential benefit exceeds the risks and anticipated costs," information on the costs
associated with the prophylactic use of antimicrobials specifically for urological surgery
cannot be easily obtained, however, data from other surgical disciplines can guide us in
making decisions. For example, the use of prophylaxis in transurethral resection of the
prostate, where there are multiple clinical trials and it is recommended the use of
prophylaxis with pre-procedure third-generation cephalosporins. On the contrary, excessive
and / or inappropriate antimicrobial prophylaxis increases costs, which can be reduced with
measures to improve commitment with evidence-based recommendations. In general, the financial
costs of prophylaxis are controlled using the least expensive and safest effective agent for
the shortest time that is compatible with good clinical practice.

There are currently few randomized clinical studies (conducted more than 25 years ago) on the
subject. In 1988 a randomized clinical trial was conducted with 243 patients undergoing TURB,
three perioperative doses of cefradine were compared with placebo, observing a significant
reduction in the rate of bacteriuria. However, no similar randomized clinical trials have
been performed, as well as for other cystoscopic procedures that involve transurethral
manipulation (bladder biopsy, ureteral catheterization, laser prostatectomy, etc.). For this
reason, updated and available evidence is required for this widely used procedure.

The American Urological Association and the Japanese guidelines recommend the use of
fluoroquinolones, trimethoprim, penicillins, first or second generation cephalosporins or
aminoglycosides before the start of TURB as an antimicrobial prophylaxis In countries with
poor control of the use of antimicrobials such as Mexico, there is a tendency towards
bacterial resistance, placing fluoroquinolones as the second line of treatment for urinary
tract infection. Therefore, the use of fluoroquinolone-based regimens, a pillar of
prophylaxis guidelines, is increasingly ineffective due to a constant increase in resistant
multidrug gram negative bacteria. The same applies with second and third generation
cephalosporins, which also have resistance problems.

In 2007 a randomized clinical trial was performed and the effectiveness of fosfomycin against
cefotiam to prevent infections associated with urological surgery was compared ,the response
rates reported were 92.9% for fosfomycin and 94.9% for cefotiam in patients with
transurethral surgery. Therefore, fosfomycin trometamol may be a potential option for
urological procedures, due to its high effectiveness against resistant multidrug gram
negative bacteria and its favorable pharmacokinetic parameters.

The aim of the study is to provide evidence to help clarify the usefulness and feasibility of
antimicrobial prophylaxis, being fosfomycin trometamol an antibiotic that meets the necessary
characteristics for this intervention. Therefore it will contribute to the characterization
of the population that undergoes this procedure, which includes the description of risk
factors and microbiological characteristics, such as the identification of emerging resistant
strains. The results obtained will contribute towards the decision-making of this and other
cytoscopic procedures due to the similarities in terms of invasiveness and possible tissue
trauma, suggesting that the data regarding transurethral bladder resection can reasonably be
extrapolated to other cystoscopic procedures with manipulation. The above will be compared
with the antimicrobial prophylaxis that usually occurs in the Instituto Nacional de Ciencias
Medicas y Nutricion Salvador Zubiran which is based on aminoglycosides (Amikacin)
administered in anesthetic induction before the surgical procedure.

• Overall Status
  Recruiting
• Start Date
  January 1, 2020
• Phase
  Phase 2
• Study Type
  Interventional