Clinical trial NCT02384200
Conditions: Nephrolithiasis Urinary Tract Infections
Sponsor: University of California, San Diego
Start date: 2015-03-01; Completion date: 2019-06-01
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
When patients are going to have surgery to remove large kidney stones (percutaneous nephrolithotomy \[PCNL\]), it is not clear whether the patients benefit from a course of prophylactic preoperative oral antibiotics; currently both the use of prophylactic preoperative oral antibiotics and no prophylactic oral antibiotics are considered to be within standard-of-care.

This study will randomize patients to preoperative prophylactic antibiotics or no antibiotics to determine if the use of preoperative prophylactic antibiotics decreases the postoperative risk of localized urinary tract infection (UTI) and/or systemic infection that started in the urinary tract (sepsis or urosepsis).

Detailed description:
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.

Arms: arm 1: 1 week course of preoperative nitrofurantoin monohydrate/macrocrystalline capsules 100 milligrams twice daily starting 1 week prior to planned kidney stone surgery (PCNL).

In addition, each patient receives a 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. arm 2: Each patient does receive a 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.
Interventions: intervention 1: nitrofurantoin monohydrate/macrocrystalline capsules intervention 2: ampicillin intervention 3: gentamicin intervention 4: vancomycin intervention 5: ceftriaxone
Intervention descriptions: intervention 1: 1 week course of preoperative nitrofurantoin monohydrate/macrocrystalline capsules 100 milligrams twice daily intervention 2: IV (2 g) intervention 3: IV (5 mg/kg) intervention 4: IV (1 g) intervention 5: IV (2 g)

Protocol documents:
Prot_SAP_000.pdf: 
A Randomized Trial of Preoperative Prophylactic Antibiotics Prior to Kidney Stone 
Surgery (Percutaneous Nephrolithotomy [PCNL]) 
 
NCT #02384200 
 
Document Date -  July 3, 2016 
 
 
 
 


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 (trade name Macrobid) 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.  Only study staff at the coordinating institution (UCSD) will have access 
to the full allocation sequence.  i.e. 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 demographics, 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 120 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 weeks postoperative imaging. Patients will be followed 
during routine clinical visits as part of their continuing care.  
 
b. 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. 
 
c. 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. 
 
d. 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 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 Presure (SBP) < 90 mmHg, Mean Arterial Pressure < 70 mmHg, 
or SBP decrease >40 mmHg in adults 
▪ 
WBC >12000 or < 4000 
 
 
e. 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. 
 
f. 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 a 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 increased 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. 
 
g. 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 we seek 
to study which are signs and symptoms of sepsis and septic shock.