A Randomized Trial of Preoperative Prophylactic Antibiotics Prior to Kidney Stone Surgery (Percutaneous Nephrolithotomy [PCNL])

1. Study Design or Overview This study will be a multi-institutional randomized, controlled
clinical trial of a course of a 1 week course of preoperative nitrofurantoin
monohydrate/macrocrystalline capsules 100 milligrams twice daily leading up to PCNL. The
control group will be no preoperative oral antibiotics. The participating institutions
are academic medical centers in the United States and Canada that are part of the EDGE
(Endourologic Disease Group of Excellence) research consortium, a research collaborative
that has the goal of producing high quality, multi-institutional studies of
nephrolithiasis. Separate IRB approvals will be obtained at each institution. UCSD will
be the coordinating institution. Member institutions of EDGE maintain frequent email
contact with one another and hold a monthly teleconference to discuss safety updates,
interim results, issues with accrual, and modifications to research protocols and
consents (if necessary).

Treatment Assignment:

Patients will be assigned to control or intervention arm based on a predetermined
allocation sequence that will be generated by a computerized random number generator.
Patients will be stratified by institution in permuted blocks of varying size. No
clinical staff involved in recruiting and consenting patients for the study at UCSD or
other participating institutions will have knowledge of the allocation sequence at their
institution prior to enrollment of each patient. To further aid allocation concealment,
the block size will be varied.

Standard of care procedures:

Patients will be identified based on clinic visits or hospital admission. All patients
will be counseled on standard treatment options— extracorporeal shock wave lithotripsy
(ESWL), percutaneous nephrolithotomy (PCNL) and ureteroscopy (URS). The discussion
regarding treatment options and subsequent care will not deviate from routine care.
Patients consenting for PCNL will be considered for enrollment into the study and will
be enrolled to have data collected prospectively. Patients will be consented prior to
prescription of antibiotics and to the surgery for collection of demographic, disease,
perioperative, and postoperative data. Abdominal pelvic computed tomography (CT), if not
already obtained, will be used to delineate pre-operative stone size and for
preoperative planning. If the patient does not consent to the study the use of
antibiotics will be based on the routine clinical practice of the treating urologist.
Both prophylaxis with preoperative antibiotics and no prophylaxis (i.e. periprocedural
only) are considered standard of care and this study will examine the difference between
these two common practices.

Investigational portion of treatment:

Patients randomized to the intervention arm will be prescribed nitrofurantoin
monohydrate/macrocrystalline 100 mg twice daily for 7 days prior to PCNL with the final
day of prophylactic course being 1 day prior to surgery. Nitrofurantoin
monohydrate/macrocrystalline is currently indicated for the treatment of acute
uncomplicated urinary tract infections. Antibiotics the day of surgery will be a dose of
ampicillin IV (2 g) and gentamicin IV (5 mg/kg) within 60 minutes of surgery start time.
Patients with penicillin allergy will receive vancomycin IV (1 g) instead of ampicillin
and patients with gentamicin/aminoglycoside allergy will receive ceftriaxone IV (2 g)
instead of gentamicin. Postoperative antibiotics in the absence of infection will be <24
hours of IV antibiotics. Control patients will receive perioperative ampicillin IV (2 g)
and gentamicin IV (5 mg/kg) (or vancomycin(1 g) /ceftriaxone (2 g), if indicated) as in
the intervention arm, but control patients will not be prescribed a course of
preoperative oral antibiotics. Central randomization will take place with UCSD as the
lead site. Randomization will occur in block randomization in block sizes of 4.

Standard of care procedures Patients will have PCNL performed in standard fashion,
without deviation from standard of care. Per the usual practice of the treating surgeon,
percutaneous access into the kidney will be obtained either by Interventional Radiology
or by the operating surgeon. At time of surgery, urine from the renal pelvis, urine from
the bladder, and the stone itself will be sent for culture. Placement of renal drainage
devices (ureteral stents, nephrostomy tubes, nephroureteral stents) will be left up to
the discretion of the surgeon. Post-operatively, the patients will be admitted to the
hospital and monitored per usual clinical procedure. Pre-operative CBC, basic metabolic
panel (chem 7) as well as Postoperative day 1, a CBC, basic metabolic panel (chem 7).
further laboratory tests will be dictated by the patients' clinical status as per the
standard of care—i.e. for patients that exhibit signs of sepsis such as tachycardia
(>90/min), low systolic blood pressure (<90 mmHg), fever >38.3C, hypothermia <36C,
altered mental status, respiratory rate>20 min or leukocytosis >12000 or leukopenia
(<4000), further urine culture, blood culture and serum lactate will be obtained (as per
standard of care).

The patient will be discharged from the hospital per the usual clinical protocols.
Post-discharge the patient will be seen in clinic 1-12 weeks after surgery. Patients
will undergo a non-contrast CT abdomen/pelvis, an abdominal plain radiograph, and/or a
renal ultrasound during this postoperative period.

Demographic fields that will be obtained preoperatively include age, race, gender, ASA
(American Society of Anesthesiologists) score (for comorbidity assessment), body mass
index (BMI), and prior stone disease. Disease fields that will be obtained include stone
size (maximal axial and coronal dimensions), degree of hydronephrosis
(mild/moderate/severe), and history of diabetes mellitus, history of cardiac disease,
hypertension, prior urinary tract infection, history of bowel diversion, or neurogenic
bladder.

Perioperative fields will include OR (surgical) time, type of anesthesia, number of
access tracts, use of internalized ureteral stent, nephrostomy tube, or nephroureteral
stent, estimated blood loss, and intraoperative complications. Postoperative fields will
include postoperative maximum body temperature, heart rate, respiratory rate, urine
culture results, stone culture results, stone composition, white blood cell count, serum
lactate, postoperative serum creatinine, need for admission to intensive care unit,
hospital length of stay (LOS), and stone-free status at 1-12 week postoperative imaging.
Patients will be followed during routine clinical visits as part of their continuing
care.

2. Data Collection Data will be collected by each participating site and entered into a
designated and shared REDCap (Research Electronic Data Capture) database. All patient
specific information will be de-identified and the database will be password protected
with access rights restricted to the lead investigator or their team at each site. Data
collectors will be blinded from treatment allocation.

3. Data Handling The electronic data will be stored in the external REDCap database. This
database will be saved at a separate server that allows the study staff from non-UCSD
sites to contribute their database. Study staff will create the database and is
responsible for analyzing the study data. The coordinator at each site will perform data
entry.

4. Data Analysis The summary statistics will be used to describe the data. Mean/95%
confidence intervals will be reported for continuous variables, and frequency/percentage
will be reported for nominal variables. The primary outcome, rate of postoperative
sepsis, and the corresponding 95% confidence interval (CI) will be reported, and
compared between the intervention and control groups at the for the postoperative period
using a Chi-squared test. Secondary outcomes will include rate of nonseptic bacteruria,
stone-free rate, and LOS and will be compared with using Chi-squared tests or t-test as
indicated. The patient characteristics and outcomes between those who have one-year
follow up records and those who do not will also be investigated. Using 2-sided P
values, statistical significance will be set at p≤0.05.

Sepsis will be defined by the defined by the 2012 International Guidelines for
Management of Severe Sepsis and Septic Shock where 2 or more of the following variables
are present and temporally associated

- Temp > 38.3 C or <36 C

- Heart Rate > 90/min (at least 12 hrs after surgery)

- Respiratory Rate > 20/min (at least 12 hrs after surgery)

- Altered mental status: defined as lack of orientation to either name, place, or
time/date.

- Systolic Blood Pressure (SBP) < 90 mmHg, Mean Arterial Pressure < 70 mmHg, or SBP
decrease >40 mmHg in adults

- WBC >12000 or < 4000

5. Feasibility and Time Frame This study enrollment period will be 2 years, with presumed
enrollment expected to be completed prior to that date. Each site is a high volume stone
center that performs more than 30 PCNLs per year.

6. Strengths This study is unique in that it randomizes patients at low to moderate risk of
postoperative infection and it uses the most updated definition of sepsis as the primary
outcome. The limitations of previous studies have been lack of randomization, exclusion
of patients at moderate-high risk of infection, and less contemporary definitions of
sepsis. It aims to answer very important and relevant questions as it pertains both to
the surgical management of kidney stone disease and to the prophylactic use of
preoperative antibiotics in patients with an increase risk of infection. It will also
represent a broad geographic distribution of patients from the US and Canada due to the
location of the participating sites.

7. Limitations The inclusion of a placebo pill would strengthen the study but was not able
to be included due to logistical difficulties with obtaining a placebo of identical
appearance that would have been adequate for blinding. Furthermore, there is little
benefit of a "placebo effect" for the objective outcomes that the investigators seek to
study which are signs and symptoms of sepsis and septic shock.

Inclusion Criteria:

- Renal stone of any size for which PCNL is recommended

Exclusion Criteria:

- eGFR < 60 mL/min/1.73 m2

- cirrhosis and/or hepatitis

- Pregnancy

- Positive preoperative urine culture within 2 weeks

- History of temperature >=38.3 C associated with nephrolithiasis or sepsis thought to
be due to urinary source within 12 months prior to randomization

- Current internalized ureteral stent, nephrostomy tube, or nephroureteral stent

- Antibiotic use within 2 weeks prior to randomization

- Severe hydronephrosis (defined by > =2cm in largest dimension) preoperatively as
judged on CT scan, abdominal X-ray, ultrasound, or fluoroscopy.