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Urinary Tract Infections: Difference between revisions

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** There may be serious difficulties in diagnosing spinal cord–injured and elderly patients who may be unable to localize the site of their discomfort.
** There may be serious difficulties in diagnosing spinal cord–injured and elderly patients who may be unable to localize the site of their discomfort.
* '''Chronic pyelonephritis:''' a shrunken, scarred kidney, diagnosed by morphologic, radiologic, or functional evidence of renal disease that may be post-infectious but is frequently not associated with UTI.
* '''Chronic pyelonephritis:''' a shrunken, scarred kidney, diagnosed by morphologic, radiologic, or functional evidence of renal disease that may be post-infectious but is frequently not associated with UTI.
* '''Uncomplicated vs. complicated infection'''
* '''<span style="color:#ff0000">Uncomplicated vs. complicated infection'''
** '''Uncomplicated: infection in a healthy patient with a structurally and functionally normal urinary tract. The majority of these patients are women'''
** '''<span style="color:#ff0000">Uncomplicated: infection in a healthy patient with a structurally and functionally normal urinary tract. The majority of these patients are women'''
** '''Complicated UTIs requires either (5):[https://www.auanet.org/meetings-and-education/for-medical-students/medical-students-curriculum/adult-uti §]'''
** '''<span style="color:#ff0000">Complicated UTIs requires either (5):[https://www.auanet.org/meetings-and-education/for-medical-students/medical-students-curriculum/adult-uti §]'''
**# '''Anatomic or functional abnormality of urinary tract (outlet obstruction, stone disease, diverticulum, neurogenic bladder, VUR etc.)'''
**# '''<span style="color:#ff0000">Anatomic or functional abnormality of urinary tract (outlet obstruction, stone disease, diverticulum, neurogenic bladder, VUR etc.)'''
**# '''Urinary instrumentation or foreign bodies in the urinary tract (i.e. catheters, stents, nephrostomy tubes)'''
**# '''<span style="color:#ff0000">Urinary instrumentation or foreign bodies in the urinary tract (i.e. catheters, stents, nephrostomy tubes)'''
**# '''Systemic disease (renal insufficiency, diabetes, immunodeficiency, organ transplantation)'''
**# '''<span style="color:#ff0000">Systemic disease (renal insufficiency, diabetes, immunodeficiency, organ transplantation)'''
**# '''Pregnancy'''
**# '''<span style="color:#ff0000">Pregnancy'''
**# '''Multi–drug resistant bacteria'''
**# '''<span style="color:#ff0000">Multi–drug resistant bacteria'''
* Chronic is a poor term that should be avoided in the context of UTIs, except for chronic pyelonephritis or bacterial prostatitis, because the duration of the infection is not defined.
* Chronic is a poor term that should be avoided in the context of UTIs, except for chronic pyelonephritis or bacterial prostatitis, because the duration of the infection is not defined.
* UTIs may also be defined by their relationship to other UTIs:
* UTIs may also be defined by their relationship to other UTIs:
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=== Labs ===
=== Labs ===
* '''Urine collection'''
 
** '''Voided and catheterized specimens'''
==== Urine collection ====
*** '''Males'''
* '''Voided and catheterized specimens'''
**** '''In circumcised males, voided specimens require no preparation. For males who are not circumcised, the foreskin should be retracted and the glans penis washed with soap and then rinsed with water before specimen collection.'''
** '''Males'''
**** '''The first 10 mL of urine (representative of the urethra) and a midstream specimen (representative of the bladder) should be obtained.'''
*** '''In circumcised males, voided specimens require no preparation. For males who are not circumcised, the foreskin should be retracted and the glans penis washed with soap and then rinsed with water before specimen collection.'''
**** '''Prostatic fluid is obtained by performing digital prostatic massage''' and collecting the expressed prostatic fluid on a glass slide. In addition, '''collection of the first 10 mL of voided urine after massage will reflect the prostatic fluid added to the urethral specimen.'''
*** '''The first 10 mL of urine (representative of the urethra) and a midstream specimen (representative of the bladder) should be obtained.'''
**** Catheterization of a male patient for urine culture is not indicated unless the patient cannot urinate.
*** '''Prostatic fluid is obtained by performing digital prostatic massage''' and collecting the expressed prostatic fluid on a glass slide. In addition, '''collection of the first 10 mL of voided urine after massage will reflect the prostatic fluid added to the urethral specimen.'''
*** '''Females'''
*** Catheterization of a male patient for urine culture is not indicated unless the patient cannot urinate.
**** '''In females, contamination of a midstream urine specimen with introital bacteria and WBCs is common, particularly when the woman has difficulty spreading and maintaining separation of the labia. Therefore, females should be instructed to spread the labia, wash and cleanse the periurethral area with moist gauze, and then collect a midstream urine specimen.'''
** '''Females'''
***** '''Cleansing with antiseptics is not recommended''' because they may contaminate the voided specimen and provide a false-negative urine culture.
*** '''In females, contamination of a midstream urine specimen with introital bacteria and WBCs is common, particularly when the woman has difficulty spreading and maintaining separation of the labia. Therefore, females should be instructed to spread the labia, wash and cleanse the periurethral area with moist gauze, and then collect a midstream urine specimen.'''
**** '''The voided specimen is contaminated if it shows evidence of vaginal epithelial cells and lactobacilli on urinalysis,''' and a catheterized specimen should be collected.
**** '''Cleansing with antiseptics is not recommended''' because they may contaminate the voided specimen and provide a false-negative urine culture.
** '''Suprapubic aspiration'''
*** '''The voided specimen is contaminated if it shows evidence of vaginal epithelial cells and lactobacilli on urinalysis,''' and a catheterized specimen should be collected.
*** '''Advantage: highly accurate'''
* '''Suprapubic aspiration'''
*** '''Disadvantages:''' '''some morbidity'''
** '''Advantage: highly accurate'''
*** '''Limited clinical usefulness''' except for a patient who cannot urinate on command such as patients with spinal cord injuries and newborns
** '''Disadvantages:''' '''some morbidity'''
*** Steps to perform procedure available in CW11 page 250
** '''Limited clinical usefulness''' except for a patient who cannot urinate on command such as patients with spinal cord injuries and newborns
** '''Bag specimens'''
** Steps to perform procedure available in CW11 page 250
*** '''Unreliable and unacceptable for diagnosis of UTI in high-risk populations and infants'''.
* '''Bag specimens'''
**** '''Generally, if a UTI is suspected in a child who is not yet toilet trained, only a catheterized or needle-aspirated specimen is acceptable for diagnosis''' because bagged urinary specimens have an unacceptably high false-positive rate.
** '''Unreliable and unacceptable for diagnosis of UTI in high-risk populations and infants'''.
***** Under special collection circumstances when the perineum is cleaned well and the bag removed and processed promptly after voiding, a bagged specimen or even a diaper specimen that shows no growth is useful in eliminating bacteriuria as a diagnosis.
*** '''Generally, if a UTI is suspected in a child who is not yet toilet trained, only a catheterized or needle-aspirated specimen is acceptable for diagnosis''' because bagged urinary specimens have an unacceptably high false-positive rate.
* '''Urinalysis (UA)'''
**** Under special collection circumstances when the perineum is cleaned well and the bag removed and processed promptly after voiding, a bagged specimen or even a diaper specimen that shows no growth is useful in eliminating bacteriuria as a diagnosis.
** '''Provides rapid identification of bacteria and WBCs and presumptive diagnosis of UTI'''
 
*** '''Assess for bacteria, epithelial cells, pyuria, hematuria, nitrites'''
==== Urinalysis (UA) ====
*** '''Diagnosis is confirmed by urine culture'''
* '''Provides rapid identification of bacteria and WBCs and presumptive diagnosis of UTI'''
**** UA does not replace urine culture and may be more relevant for screening in asymptomatic patients
** '''Assess for bacteria, epithelial cells, pyuria, hematuria, nitrites'''
** Usually, the sediment from an ≈5-10-mL specimen obtained by centrifugation for 5 minutes at 2000 rpm is analyzed.
** '''Diagnosis is confirmed by urine culture'''
** '''Bacteriuria'''
*** UA does not replace urine culture and may be more relevant for screening in asymptomatic patients
*** Definition of bacteriuria: presence of bacteria in the urine, which is normally free of bacteria
* Usually, the sediment from an ≈5-10-mL specimen obtained by centrifugation for 5 minutes at 2000 rpm is analyzed.
**** The term "significant bacteriuria" has a clinical connotation and is used to describe the number of bacteria in a suprapubically aspirated, catheterized, or voided specimen that exceeds the number usually caused by bacterial contamination of the skin, the urethra, or the prepuce or introitus, respectively.
* '''Bacteriuria'''
*** '''Can be symptomatic or asymptomatic'''
** Definition of bacteriuria: presence of bacteria in the urine, which is normally free of bacteria
*** '''Found in > 90% of infections with counts of ≥105 colony-forming units (cfu) per milliliter of urine and''' '''is a highly specific finding'''.
*** The term "significant bacteriuria" has a clinical connotation and is used to describe the number of bacteria in a suprapubically aspirated, catheterized, or voided specimen that exceeds the number usually caused by bacterial contamination of the skin, the urethra, or the prepuce or introitus, respectively.
**** Bacteria are usually not detectable microscopically with lower cfu (102-104/mL).
** '''Can be symptomatic or asymptomatic'''
*** '''Causes of false-negative UA and culture:'''
** '''Found in > 90% of infections with counts of ≥105 colony-forming units (cfu) per milliliter of urine and''' '''is a highly specific finding'''.
***# '''Early in an infection'''
*** Bacteria are usually not detectable microscopically with lower cfu (102-104/mL).
***# '''In context of increased fluid intake and subsequent dilute urine'''
** '''Causes of false-negative UA and culture:'''
**** '''A negative urinalysis for bacteria never excludes the presence of bacteria'''
**# '''Early in an infection'''
*** '''Causes of false-positive UA and culture:'''
**# '''In context of increased fluid intake and subsequent dilute urine'''
***# '''Contamination of an abacteriuric specimen during collection'''
*** '''A negative urinalysis for bacteria never excludes the presence of bacteria'''
***#* '''Contamination can be considered if numerous squamous epithelial cells''' (indicative of preputial, vaginal, or urethral contaminants) '''are present'''
** '''Causes of false-positive UA and culture:'''
***#** The possibility of contamination increases as the reliability of the collection technique decreases from suprapubic aspiration to catheterization to voided specimens
**# '''Contamination of an abacteriuric specimen during collection'''
** '''Pyuria'''
**#* '''Contamination can be considered if numerous squamous epithelial cells''' (indicative of preputial, vaginal, or urethral contaminants) '''are present'''
*** '''Definition of pyuria:''' presence of white blood cells in the urine, '''generally indicative of infection and/or an inflammatory response''' of the urothelium to the bacterium, stones, or other indwelling foreign body.
**#** The possibility of contamination increases as the reliability of the collection technique decreases from suprapubic aspiration to catheterization to voided specimens
*** '''The absence of pyuria should cause the diagnosis of UTI to be questioned until urine culture results are available.'''
* '''Pyuria'''
*** '''Bacteriuria without pyuria is generally indicative of bacterial colonization without infection of the urinary tract.'''
** '''Definition of pyuria:''' presence of white blood cells in the urine, '''generally indicative of infection and/or an inflammatory response''' of the urothelium to the bacterium, stones, or other indwelling foreign body.
*** '''Sterile pyuria (pyruria without bacteriuria) warrants evaluation for tuberculosis, stones, or cancer. Many other causes§'''
** '''The absence of pyuria should cause the diagnosis of UTI to be questioned until urine culture results are available.'''
**** '''Almost any injury to the urinary tract''', from chlamydial urethritis to glomerulonephritis and interstitial cystitis, '''can elicit large numbers of fresh polymorphonuclear leukocytes'''
** '''Bacteriuria without pyuria is generally indicative of bacterial colonization without infection of the urinary tract.'''
*** '''Tests for detecting pyuria by determining leukocyte esterase activity have been developed'''
** '''Sterile pyuria (pyruria without bacteriuria) warrants evaluation for tuberculosis, stones, or cancer. Many other causes§'''
** '''Nitrites'''
*** '''Almost any injury to the urinary tract''', from chlamydial urethritis to glomerulonephritis and interstitial cystitis, '''can elicit large numbers of fresh polymorphonuclear leukocytes'''
*** '''Bacteria may convert urinary nitrates into nitrites and this may be used as evidence of UTI.'''
** '''Tests for detecting pyuria by determining leukocyte esterase activity have been developed'''
**** '''Gram-negative bacteria of the Enterobacteriaceae family (Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, or Citrobacter) commonly convert nitrates to nitrites, while Gram-positive species (enterococcus, staphylococcus) generally do not.'''
* '''Nitrites'''
***** '''One very important gram-negative exception is Pseudomonas, which does not contain the enzymatic machinery to convert nitrates to nitrites'''
** '''Bacteria may convert urinary nitrates into nitrites and this may be used as evidence of UTI.'''
** Hematuria
*** '''Gram-negative bacteria of the Enterobacteriaceae family (Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, or Citrobacter) commonly convert nitrates to nitrites, while Gram-positive species (enterococcus, staphylococcus) generally do not.'''
*** Indicator of an inflammatory response
**** '''One very important gram-negative exception is Pseudomonas, which does not contain the enzymatic machinery to convert nitrates to nitrites'''
*** Microscopic hematuria is found in 40-60% of cases of cystitis and is uncommon in other dysuric syndromes
* Hematuria
* '''Urine culture'''
** Indicator of an inflammatory response
** Techniques available (2): direct surface plating and dip slides
** Microscopic hematuria is found in 40-60% of cases of cystitis and is uncommon in other dysuric syndromes
** '''Urine must be refrigerated immediately on collection and should be cultured within 24 hours of refrigeration.'''
 
** '''A cut-off of ≥105/mL has been proposed to define significant bacteruria [from a midstream specimen]'''
==== Urine culture ====
*** '''However, 20-40% of women with symptomatic UTIs present with bacteria counts of 102-104 cfu/mL of urine; therefore, in dysuric patients, an appropriate threshold value for defining significant bacteriuria is 102 cfu/mL of a known pathogen.'''
* Techniques available (2): direct surface plating and dip slides
*** The ≥105 cut-off may also lead to overdiagnosis in patients with contaminated urine.
* '''Urine must be refrigerated immediately on collection and should be cultured within 24 hours of refrigeration.'''
* Localization
* '''A cut-off of ≥105/mL has been proposed to define significant bacteruria [from a midstream specimen]'''
** Kidney
** '''However, 20-40% of women with symptomatic UTIs present with bacteria counts of 102-104 cfu/mL of urine; therefore, in dysuric patients, an appropriate threshold value for defining significant bacteriuria is 102 cfu/mL of a known pathogen.'''
*** Fever and flank pain are common in pyelonephritis, but can also occur in infections localized to the bladder
** The ≥105 cut-off may also lead to overdiagnosis in patients with contaminated urine.
*** Ureteral catherization allows separation of bacterial persistence into upper and lower urinary tracts and also separation of laterality of kidney infection.
 
==== Localization ====
* Kidney
** Fever and flank pain are common in pyelonephritis, but can also occur in infections localized to the bladder
** Ureteral catherization allows separation of bacterial persistence into upper and lower urinary tracts and also separation of laterality of kidney infection.


=== Imaging ===
=== Imaging ===
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*# '''Unusual infecting organisms, such as tuberculosis, fungus, or urea-splitting organisms (e.g., Proteus, Pseudomonas, Klebsiella, Staphylococcus, and Mycoplasma)'''
*# '''Unusual infecting organisms, such as tuberculosis, fungus, or urea-splitting organisms (e.g., Proteus, Pseudomonas, Klebsiella, Staphylococcus, and Mycoplasma)'''
* '''Options: ultrasound, CT/MRI, VUCG (to assess for vesicoureteral reflux), and radionuclide studies'''
* '''Options: ultrasound, CT/MRI, VUCG (to assess for vesicoureteral reflux), and radionuclide studies'''
== Management ==
=== Antibiotics ===
* Factors to consider when selecting
** Empirical therapy include whether the infection is complicated or uncomplicated, spectrum of activity of the drug against the probable pathogen, history of hypersensitivity, potential side effects, and cost
** Duration of therapy include the extent and duration of tissue invasion, bacterial concentration in urine, achievable urine concentration of the antimicrobial agent, and risk factors that impair the host and natural defense mechanisms
'''Principles of antibiotic therapy'''
* '''<span style="color:#ff0000">Antimicrobials are excreted in a concentrated form compared to their serum concentrations'''
** Resolution of infection is associated with the susceptibility of the bacteria to the concentration of the antimicrobial agent in the urine.
** '''Susceptibility testing is based on concentrations obtained in the serum'''
*** '''Some antibiotics do not achieve adequate serum concentration levels to be considered effective for bacteriemia, but could be effective at its achievable urinary concentration.'''
**** For example, E. Coli susceptible testing may show resistance to amoxicillin, even though amoxicillin may actually be effective for urinary E. Coli because of the high concentrations achieved.
*** '''The concentration of the antimicrobial agent achieved in blood is not important in treatment of uncomplicated UTIs. However, blood levels are critical in patients with bacteremia and febrile urinary infections consistent with parenchymal involvement of the kidney and prostate'''
** '''<span style="color:#ff0000">In patients with renal insufficiency, dosage modifications are necessary for antibiotics that are renally cleared, including:'''
**# '''<span style="color:#ff0000">Ciprofloxacin'''
**# '''<span style="color:#ff0000">Nitrofurantoin'''
**# '''<span style="color:#ff0000">Trimethoprim/sulfamethoxazole'''
**# '''<span style="color:#ff0000">Trimethoprim'''
**# '''<span style="color:#ff0000">Amoxicillin'''
**# '''<span style="color:#ff0000">Piperacillin/tazobactam'''
**# '''<span style="color:#ff0000">Cephalexin'''
**# '''<span style="color:#ff0000">Cefuroxime'''
**# '''<span style="color:#ff0000">Levofloxacin'''
**# '''<span style="color:#ff0000">Clarithromycin'''
**# '''<span style="color:#ff0000">Tetracyclin'''
*** '''In renal failure, the kidneys may not be able to concentrate an antimicrobial agent in the urine; hence, difficulty in eradicating bacteria may occur.'''
** Urinary tract obstruction may reduce concentration of antimicrobial agents within the urine.
* '''Bacterial resistance'''
** '''Mechanisms (3)'''
**# '''Inherited chromosomal-mediated'''
**# '''Acquired chromosomal'''
**# '''Extrachromosomal (plasmid)-mediated'''
*** '''Inherited chromosomal resistance'''
**** Exists in a bacterial species because of the absence of the proper mechanism on which the antimicrobial agent can act. For example, '''Proteus and Pseudomonas species are always resistant to nitrofurantoin'''
*** '''Acquired chromosomal resistance'''
**** '''Caused by exposure of an organism to antimicrobial agents'''
*** '''Extrachromosomal-mediated resistance'''
**** '''May be acquired and transferable via plasmids, which contain the genetic material for the resistance'''
***** '''This so-called R-factor resistance occurs in the bowel flora and is much more common than selection of pre-existing mutants in the urinary tract.'''
***** '''All antibiotic classes are capable of causing plasmid-mediated resistance. However, for the fluoroquinolones, resistance is rarely transmitted by plasmids, and nitrofurantoin plasmid-mediated resistance has not been reported.'''
****** '''Clinical implication: because the bowel flora is the major reservoir for bacteria that ultimately colonize the urinary tract, infections that occur after antibiotic therapy and that can cause plasmid-mediated resistance are commonly caused by organisms with multidrug resistance. However, resistant E. coli in the bowel flora that infect the urinary tract almost always show susceptibility to nitrofurantoin or to the quinolones.'''
** '''Antibiotic resistance is also influenced by the duration and amount of antibiotic agent used.'''
==== Mechanism of action of common antimicrobials used in the treatment of urinary tract infections ====
{| class="wikitable"
|'''<span style="color:#ff0000">Drug or drug class'''
|'''<span style="color:#ff0000">Mechanism of action'''
|'''Mechanisms of drug resistance'''
|-
|'''<span style="color:#ff0000">β-Lactams (penicillins, cephalosporins, carbapenems, aztreonam)'''
|'''<span style="color:#ff0000">Inhibits bacterial cell wall synthesis'''
|Production of β-lactamase
Alteration in binding site of penicillin-binding protein
Changes in cell wall porin size (decreased penetration)
|-
|'''<span style="color:#ff0000">Vancomycin'''
|'''<span style="color:#ff0000">Inhibits bacterial cell wall synthesis'''
|Enzymatic alteration of peptidoglycan at different point
than target
|-
|'''<span style="color:#ff0000">Fosfomycin'''
|'''<span style="color:#ff0000">Inhibits bacterial cell wall synthesis'''
|Novel amino acid substitutions or the loss of function of transporters
|-
|'''<span style="color:#ff0000">Aminoglycosides (gentamicin, tobramycin, etc.)'''
|'''<span style="color:#ff0000">Inhibits ribosomal protein synthesis'''
|Downregulation of drug uptake into bacteria
Bacterial production of aminoglycoside-modifying enzymes
|-
|'''<span style="color:#ff0000">Clindamycin, macrolides (erythromycin, clarithromycin, azithromycin)'''
|'''<span style="color:#ff0000">Inhibits ribosomal protein synthesis'''
|
|-
|'''<span style="color:#ff0000">Quinolones (ciprofloxacin, levofloxacin, etc.)'''
|'''<span style="color:#ff0000">Inhibits bacterial DNA gyrase'''
|Mutation in DNA gyrase-binding site
Changes in cell wall porin size (decreased penetration)
Active efflux
|-
|'''<span style="color:#ff0000">Trimethoprim-sulfamethoxazole'''
|'''<span style="color:#ff0000">Competitive inhibition of dihydrofolate reductase'''
|Draws folate from environment (enterococci)
|-
|'''<span style="color:#ff0000">Nitrofurantoin'''
|'''<span style="color:#ff0000">Inhibits several bacterial enzyme systems'''
|Not fully elucidated—develops slowly with prolonged exposure
|}
==== Reliable coverage of antibiotics used in the treatment of UTIs from commonly encountered pathogens ====
{| class="wikitable"
|'''Antibiotic agent or class'''
|'''Gram-positive pathogens'''
|'''Gram-negative pathogens'''
|-
|'''Penicillins'''
|
|
|-
|'''Broad-spectrum penicillins'''
|
|
|-
| '''    Amoxicillin or ampicillin'''
|'''''Streptococcus'''''
'''Enterococci'''
|'''''Proteus mirabilis'''''
|-
| '''    Amoxicillin with clavulanate'''
|'''''Streptococcus'''''
'''Enterococci'''
|'''''Proteus, Klebsiella'''''
|-
| '''    Ampicillin with sublactam'''
|'''''Staphylococcus'' (not MRSA)'''
'''Enterococci'''
|'''''Proteus, Klebsiella'''''
'''''H. influenzae'''''
|-
|'''Anti-staphylococcal penicillins (methicillin, nafcillin, oxacillin, cloxacillin and dicloxacillin)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''
'''Not enterococci'''
|'''None'''
|-
|'''Anti-pseudomonal penicillins (piperacillin, ticaracillin)'''
|'''''Streptococcus'''''
'''Enterococci'''
|'''Most, including ''Pseudomonas'''''
|-
|'''Cephalosporins'''
|'''Not enterococci'''
|
|-
|'''First-generation cephalosporins (e.g. cefazolin, cephalexin)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''
'''Enterococci''' (CW12 p442)
|'''''E. coli, Proteus, Klebsiella'''''
|-
|'''Second-generation cephalosporins (cefamandole, cefuroxime, cefaclor)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''
|'''''E. coli, Proteus, Klebsiella'''''
'''''H. influenzae'''''
|-
|'''Second-generation cephalosporins (cefoxitin, cefotetan)'''
|'''''Streptococcus'''''
|'''''E. coli, Proteus''''' (including indole-positive), '''''Klebsiella'''''
'''''H. influenzae'''''
|-
|'''3rd-generation cephalosporins (ceftriaxone)'''
|'''''Streptococcus'''''
'''''Staphylococcus'' (not MRSA)'''
|'''Most, excluding ''P. aeruginosa'''''
|-
|'''3rd-generation cephalosporins (ceftazidime)'''
|'''''Streptococcus'''''
|'''Most, including ''P. aeruginosa'''''
|-
|Aztreonam
|None
|Most, including ''P. aeruginosa''
|-
|'''Aminoglycosides (gentamicin, tobramycin)'''
|'''''Staphylococcus'' (urine)'''
|'''Most, including ''P. aeruginosa'''''
|-
|'''Fluoroquinolones (e.g. ciprofloxacin)'''
|'''''Streptococcus''''' ''(depending which fluoroquinolone)''
'''Not enterococci'''
|'''Most, including ''P. aeruginosa'''''
|-
|'''Nitrofurantoin'''
|'''''Staphylococcus'' (not MRSA)'''
'''Enterococci'''
|'''Many Enterobacteriaceae (not ''Klebsiella, Proteus)'''''
'''''Does not cover P. aeruginosa, Providencia, Serratia, Acinetobacter'''''
|-
|'''Fosfomycin'''
|'''Enterococci'''
Variable activity against s. saprophyticus
|'''Most Enterobacteriaceae''' (variable activity against Klebsiella and Enterobacter)
'''Does not cover ''P. aeruginosa'')'''
|-
|Pivmecillinam
|None
|Most, excluding ''P. aeruginosa''
|-
|'''Trimethoprim-sulfamethoxazole'''
|'''''Streptococcus'''''
'''''Staphylococcus'''''
'''Not enterococci'''
|'''Most Enterobacteriaceae'''
'''Does not cover ''P. aeruginosa'''''
|-
|'''Vancomycin''' (can be used in penicillin allergy for gram-positive coverage)
|'''All, including MRSA'''
|'''None'''
|-
|'''Clindamycin''' (can be used in penicillin allergy for gram-positive coverage)
|'''''Streptococcus'''''
'''''Staphylococcus'''''
'''''NOT Enterococci'''''
|'''Anaerobes'''
'''NOT Enterobacteriaceae'''
|-
|'''Macrolides (clarithromycin, erythromycin, azithromycin)'''
|
|
|-
|'''Carbapenams (ertapenem, imipenem, meropenem)'''
|
|'''Ertapenam has weak pseudomonas coverage compared to meropenam'''
|}
==== Common adverse reactions, precautions, and contraindications for antibiotics used in treatment of UTIs ====
{| class="wikitable"
|'''Drug or drug class'''
|'''Common adverse reactions'''
|'''Precautions and contraindications'''
|-
|'''Amoxicillin or ampicillin'''
'''Ampicillin with sulbactam'''
|
** '''Hypersensitivity (immediate or delayed)'''
** '''Diarrhea (especially with ampicillin), GI upset'''
** '''Antimicrobial-associated pseudomembranous colitis'''
** '''Maculopapular rash (not hypersensitivity)'''
** '''Decreased platelet aggregation'''
|
** '''Increased risk of rash with concomitant viral disease,allopurinol therapy'''
|-
|'''Amoxicillin with clavulanic acid'''
|
** '''Increased diarrhea, GI upset'''
|
|-
|'''Anti-staphylococcal penicillins'''
|
** '''Same as with amoxicillin/ampicillin'''
** '''GI upset (with oral agents)'''
** '''Acute interstitial nephritis (especially withmethicillin)'''
|
|-
|'''Anti-pseudomonal penicillins'''
|
** '''Same as with amoxicillin/ampicillin'''
** '''Hypernatremia (these drugs are given as sodium salt; especially carbenicillin, ticarcillin)'''
** '''Local injection site reactions'''
|
** '''Use with caution in patients very sensitive to sodiumloading'''
|-
|'''Cephalosporins'''
|
** '''Hypersensitivity (less than with penicillins)'''
** '''GI upset (with oral agents)'''
** '''Antimicrobial-associated pseudomembranous colitis'''
** '''Local injection site reactions'''
** '''Positive Coombs test'''
** '''Decreased platelet aggregation (especially''' '''with cefotetan, cefamandole, cefoperazone)'''
|
** '''Avoid in patients with immediate hypersensitivity to penicillins; may use with caution in patients with delayed hypersensitivity reactions'''
** '''Ceftriaxone is contraindicated in neonates'''
|-
|Aztreonam
|
** Hypersensitivity (less than with penicillins)
|
** <1% incidence of cross-reactivity in penicillin- or cephalosporin-allergic patients; may be used with caution in these patients
|-
|'''Aminoglycosides'''
'''(gentamicin, tobramycin)'''
|
** '''Ototoxicity: vestibular and auditorycomponents'''
** '''Nephrotoxicity: nonoliguric azotemia'''
** '''Neurotoxicity: neuromuscular blockade with high levels'''
|
** '''Avoid in pregnant patients, except in pyelonephritis.'''
** '''Avoid, if possible, in patients with severely impaired renal function, diabetes, or hepatic failure'''
** '''Use with caution in myasthenia gravis patients (owing to potential for neuromuscular blockade)'''
** '''Use with caution with other potentially ototoxic andnephrotoxic drugs.'''
|-
|'''Fluoroquinolones'''
|
** '''<span style="color:#ff0000">Tendon rupture</span>''' (incidence 20 cases/100,000), should be discontinued at the first sign of tendon pain
** '''<span style="color:#ff0000">Aortic rupture</span>''' (incidence 20 cases/100,000), should be discontinued at the first sign of tendon pain
** '''<span style="color:#ff0000">QT interval prolongation;'''should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia or hypomagnesemia, and patients receiving some antiarrhythmic agents
** '''Photosensitivity'''
** '''Mild GI effects'''
** '''Central nervous system effects, including''' '''dizziness, tremors, confusion, mood disorder, hallucinations, light-headedness'''
** '''Hypoglycemia and hyperglycemia''' have been reported in patients treated concurrently with fluoroquinolones and anti-diabetic agents; '''avoid or monitor glucose levels closely in patients on anti-diabetic drugs'''
|
** '''Avoid in children or pregnant patients due to arthropathic effects.'''
** '''Concomitant antacid, iron, zinc, or sucralfate usedramatically decreases oral absorption'''; use another antimicrobial agent or discontinue sucralfate use while on quinolones. Space administration of quinolones from antacids, iron, or zinc products by at least 2 hr to ensure adequate absorption.
** '''Can significantly increase theophylline plasma levels; avoid quinolones or monitor theophylline levels closely.'''
** '''Can lower seizure threshold'''; avoid in patients with epilepsy and in patients with other risk factors (medications or illness) that may lower the seizure threshold.
** '''Avoid in patients receiving warfarin; can enhance warfarin effects'''; closely monitor coagulation tests.
** '''Avoid with other drugs that prolong QT interval, such as amiodarone'''
|-
|'''Fosfomycin'''
|
** '''Headache'''
** '''GI upset'''
** '''Vaginitis'''
|
|-
|Pivmecillinam
|
** Rash GI upset
|
** Use with caution in patients with penicillin hypersensitivity
|-
|'''Nitrofurantoin'''
|
** '''<span style="color:#ff0000">Pulmonary</span> hypersensitivity reactions can range from acute to chronic and include cough, dyspnea, fever, and interstitial changes [e.g. fibrosis].'''
** '''<span style="color:#ff0000">Hepatoxicity'''
** '''<span style="color:#ff0000">Peripheral neuropathy''' (especially in patients with impaired renal function, anemia, diabetes, electrolyte imbalance, vitamin B deficiency, and debilitated)
** '''<span style="color:#ff0000">GI upset'''
** '''<span style="color:#ff0000">Hemolysis in patients with G6PD deficiency'''
|
** '''Avoid in patients with decreased renal function(<50 mL/min) because adequate urine concentrations will not be achieved.'''
** '''Avoid concomitant probenecid use, which blocks renal excretion of nitrofurantoin.'''
** '''Monitor long-term patients closely.'''
** '''Avoid concomitant magnesium or quinolones, which are antagonistic to nitrofurantoin'''
** '''Can be given safely to patients receiving warfarin'''
** '''See below regarding use in pregnancy'''
|-
|'''Trimethoprim-sulfamethoxazole'''
|
** '''Hypersensitivity, rash'''
** '''GI upset'''
** '''Photosensitivity'''
** '''Hematologic toxicity (AIDS patients)'''
|
** '''Higher incidence of all adverse reactions occurs in AIDS patients and the elderly.'''
** '''Avoid TMP-SMX in pregnancy because of early potential for teratogenicity and late potential for kernicterus'''
** '''Avoid TMP-SMX in neonates due to risk of kernicterus from hyperbilirubinemia'''
** '''Trimethoprim alone should be avoided in pregnancy due to risk of megaloblastic anemia'''
** '''Trimethoprim alone can be used in neonates'''
** '''Avoid in patients receiving warfarin; can enhance warfarin effects'''; closely monitor coagulation tests.
** '''Avoid with other anti-arrhythmics, such as amiodarone'''
|-
|'''Vancomycin'''
|
** '''“Red-man syndrome”: flushing, fever, chills,''' '''rash, hypotension (histaminic effect)'''
** '''Nephrotoxicity and/or ototoxicity when combined with other nephrotoxic and/or ototoxic drugs'''
** '''Local injection site reactions'''
|
** '''Use with caution with other potentially ototoxic andnephrotoxic drugs.'''
|}
=== Characteristics of Antibiotics by Class ===
==== Aminopenicillins ====
* Ampicillin and amoxicillin have been used often in the past for the treatment of UTIs, but the '''emergence of resistance''' in 40-60% of common urinary '''isolates has lessened the usefulness of these drugs (See Toronto antibiograms''')
* '''The effects of ampicillin and amoxocillin on the normal bowel and vaginal flora can''' predispose patients to reinfection with resistant strains and '''often lead to candida vaginitis'''
* '''The addition of the β-lactamase inhibitor clavulanate to amoxicillin greatly improves activity against β-lactamase–producing bacteria resistant to amoxicillin alone. However, its high cost and frequent gastrointestinal side effects limit its usefulness.'''
* '''The extended-spectrum penicillin derivatives (e.g., pivmecillinam, piperacillin, mezlocillin, azlocillin) retain ampicillin’s activity against enterococci and offer activity against many ampicillin-resistant gram-negative bacilli'''
* '''Safe for use in pregnancy'''
==== Cephalosporins ====
* '''In general, as a group, activity is high against Enterobacteriaceae and poor against enterococci'''
* First-generation cephalosporins have greater activity against gram-positive organisms, as well as common uropathogens such as E. coli and Klebsiella pneumoniae, whereas second-generation cephalosporins have activity against anaerobes. Third-generation cephalosporins are more reliably active against community-acquired and nosocomial gram-negative organisms than other β-lactam antimicrobials.
* Use of these broad-spectrum agents should be limited complicated infections and situations in which parenteral therapy is required and resistance to standard antimicrobial agents is likely.
* '''Safe for use during pregnancy'''
* '''Ceftriaxone is contraindicated in neonates'''
==== Nitrofurantoin ====
* '''Effective against common uropathogens'''; '''not effective against Pseudomonas and Proteus'''
* Rapidly excreted in the urine but '''does not obtain therapeutic levels in most body tissues. Therefore, not useful for upper tract and complicated infections.'''
* '''Minimal effects on the resident bowel and vaginal flora''' and has been used effectively in prophylactic regimens
* Acquired bacterial resistance is exceedingly low
* '''Pregnancy'''
** '''2017 American College of Obstetricians and Gynecologists recommendations'''§''':'''
*** '''First trimester'''
**** Consider and discuss with patients the benefits as well as the potential unknown risks of teratogenesis and fetal and maternal adverse reactions.
**** '''Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available.'''
*** '''Second and third trimesters'''
**** '''Can be used as first-line agents''' for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms.
*** Contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency, or in pregnant women identified to be at risk of this condition.
** '''CW12 page 1186-1187'''
*** '''First and second trimester'''
**** '''May be used safely in patients without glucose-6-phosphate dehydrogenase deficiency'''
*** '''Third trimester'''
**** '''Should be discontinued at 35 weeks''' because of an increased risk of hemolytic anemia in the neonate.
==== Trimethoprim (TMP)-sulfamethoxazole (SMX) ====
* '''TMP alone or in combination with SMX is effective against most common uropathogens; not effective against Enterococcus and Pseudomonas.'''
** TMP alone is as effective as the combination for most uncomplicated infections and may be associated with fewer side effects; however, the addition of SMX contributes to efficacy in the treatment of upper tract infection via a synergistic bactericidal effect and may diminish the emergence of resistance and attains therapeutic levels in most tissues.
* Advantages are inexpensive and have '''minimal adverse effects on the bowel flora'''
* Disadvantages are relatively common adverse effects, consisting primarily of rashes and gastrointestinal complaints.
* '''Trimethoprim blocks the tubular secretion of creatinine.'''
** Since creatinine is produced at a steady state, the serum creatinine will rise, but the GFR does not change
* '''<span style="color:#ff0000">TMP-SMX should be avoided during pregnancy because of early potential for teratogenicity and late potential for kernicterus'''
* '''<span style="color:#ff0000">Trimethoprim alone should be avoided in pregnancy due to risk of megaloblastic anemia; trimethoprim alone can be used in neonates'''
==== Fosfomycin ====
* Effective against most uropathogens; '''not effective against Pseudomonas'''
* Effective against the majority of gram-negative organisms and vancomycin-resistant Enterococcus (VRE)
* Limited cross-resistance between most other common antibacterial agents
* Shown to be effective as a single-dose agent when used as an empirical treatment for uncomplicated cystitis
* Generally well tolerated with low incidences of GI upset and headache and very rare adverse events
==== Fluoroquinolones ====
* '''Broad spectrum of activity'''
** '''Highly effective against Enterobacteriaceae and P. aeruginosa'''
** '''Activity is also high against S. aureus and S. saprophyticus, but, in general, anti-streptococcal coverage is marginal'''
** '''Modest activity against enterococcus'''
* '''Most anaerobic bacteria are resistant to these drugs; therefore, the normal vaginal and bowel flora are not altered'''
* '''Increasing rates of resistance due to indiscriminate use of these agents'''
* Not nephrotoxic, but renal insufficiency prolongs the serum half-life, '''requires dose adjustment in patients with creatinine clearances of <30 mL/min.'''
* '''<span style="color:#ff0000">Contraindicated in children, adolescents, and pregnant or nursing women due to concerns of damage to developing cartilage'''
* '''Drug interactions''':
** '''Rare increases in the anticoagulant effects of warfarin when taken with fluoroquinolones'''.
** '''Concomitant antacid''' (containing magnesium or aluminum)''', iron, zinc, or sucralfate use dramatically decreases oral absorption'''
** Antacids containing magnesium or aluminum interfere with absorption of fluoroquinolones.
** Certain fluoroquinolones (enoxacin and ciprofloxacin) elevate plasma levels of theophylline and prolong its half-life
** '''Avoid with other drugs that prolong QT interval, such as amiodarone'''
== Bladder Infections ==
== Bladder Infections ==


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*** However, pyelonephritis, when associated with urinary tract obstruction or granulomatous renal infection, may lead rapidly to significant inflammatory complications, renal failure, or even death.
*** However, pyelonephritis, when associated with urinary tract obstruction or granulomatous renal infection, may lead rapidly to significant inflammatory complications, renal failure, or even death.


==== Acute pyelonephritis ====
==== Acute Pyelonephritis ====


===== Pathogens =====
===== Pathogens =====
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* More resistant species, such as Proteus, Klebsiella, Pseudomonas, Serratia, Enterobacter, or Citrobacter, should be suspected in patients who have recurrent UTIs, are hospitalized, have indwelling catheters, or have had recent urinary tract instrumentation.
* More resistant species, such as Proteus, Klebsiella, Pseudomonas, Serratia, Enterobacter, or Citrobacter, should be suspected in patients who have recurrent UTIs, are hospitalized, have indwelling catheters, or have had recent urinary tract instrumentation.
* Except for E. faecalis, S. epidermidis, and S. aureus, gram-positive bacteria rarely cause pyelonephritis.
* Except for E. faecalis, S. epidermidis, and S. aureus, gram-positive bacteria rarely cause pyelonephritis.
====== Differential Diagnoses ======
# '''<span style="color:#ff0000">Acute appendicitis'''
# '''<span style="color:#ff0000">Diverticulitis'''
# '''<span style="color:#ff0000">Pancreatitis'''
* '''Can cause a similar degree of pain, but the location of the pain often is different'''


===== Diagnosis and Evaluation =====
===== Diagnosis and Evaluation =====
* '''History and physical exam'''
 
** The clinical spectrum ranges from gram-negative sepsis to cystitis with mild flank pain.
====== History and Physical Exam ======
** The classic presentation is an abrupt onset of chills, fever, and unilateral or bilateral flank or costovertebral angle pain and/or tenderness. These signs and symptoms, referred to as upper tract signs, are often accompanied by LUTS such as dysuria, increased urinary frequency, and urgency
* The clinical spectrum ranges from gram-negative sepsis to cystitis with mild flank pain.
** Differential diagnoses: acute appendicitis, diverticulitis, and pancreatitis can cause a similar degree of pain, but the location of the pain often is different
* '''<span style="color:#ff0000">History'''
** On physical examination, there often is tenderness to deep palpation in the costovertebral angle
**'''<span style="color:#ff0000">Signs and Symptoms'''
* '''Laboratory'''
***'''<span style="color:#ff0000">Upper tract signs (3):'''
** CBC
***#'''<span style="color:#ff0000">Abrupt onset of chills'''
*** May have leukocytosis with a predominance of neutrophils.
***#'''<span style="color:#ff0000">Fever'''
** Urinalysis
***#'''<span style="color:#ff0000">Unilateral or bilateral flank or costovertebral angle pain and/or tenderness'''
*** Usually reveals numerous WBCs, often in clumps, and bacterial rods or chains of cocci.
***'''<span style="color:#ff0000">Often accompanied by LUTS such as (3):'''
*** '''The presence of large amounts of granular or leukocyte casts in the urinary sediment is suggestive of acute pyelonephritis.'''
***#'''<span style="color:#ff0000">Dysuria'''
** '''Urine cultures'''
***#'''<span style="color:#ff0000">Increased urinary frequency'''
*** '''Usually positive'''
***#'''<span style="color:#ff0000">Urgency'''
**** '''≈20% of patients have''' urine cultures with < 105 cfu/mL and therefore '''negative results on Gram staining of the urine'''
* '''<span style="color:#ff0000">Physical Exam'''
** '''Blood cultures'''
** '''<span style="color:#ff0000">Tenderness to deep palpation in the costovertebral angle'''
*** '''Should not be routinely obtained for the evaluation of uncomplicated pyelonephritis in females.'''
 
**** '''Positive in ≈25% of cases of uncomplicated pyelonephritis in females and the majority replicate the urine culture and do not influence decisions regarding therapy.'''
====== Labs ======
*** '''Should be performed in males and females with systemic toxicity or in those requiring hospitalization or with risk factors such as pregnancy'''
* '''<span style="color:#ff0000">CBC'''
* '''Imaging'''
** May have leukocytosis with a predominance of neutrophils.
** '''Renal US and CT are commonly used to evaluate patients initially for complicated UTIs or factors or to reevaluate patients who do not respond after 72 hours of therapy'''
* '''<span style="color:#ff0000">Urinalysis'''
** '''In patients with presumed uncomplicated pyelonephritis who will be managed as outpatients, initial radiologic evaluation can usually be deferred.'''
** Usually reveals numerous WBCs, often in clumps, and bacterial rods or chains of cocci.
*** However, if there is any reason to suspect a problem or if the patient will not have reasonable access to imaging if there should be no change in condition, renal US can rule out stones or obstruction.
** '''The presence of large amounts of granular or leukocyte casts in the urinary sediment is suggestive of acute pyelonephritis.'''
*** In patients with known or suspected complicated pyelonephritis, CT provides excellent assessment of the status of the urinary tract and the severity and extent of the infection.
* '''<span style="color:#ff0000">Urine cultures'''
** '''Usually positive'''
*** '''≈20% of patients have''' urine cultures with < 105 cfu/mL and therefore '''negative results on Gram staining of the urine'''
* '''<span style="color:#ff0000">Blood cultures'''
** '''<span style="color:#ff0000">Should not be routinely obtained for the evaluation of uncomplicated pyelonephritis in females.'''
*** '''Positive in ≈25% of cases of uncomplicated pyelonephritis in females and the majority replicate the urine culture and do not influence decisions regarding therapy.'''
** '''Should be performed in males and females with systemic toxicity or in those requiring hospitalization or with risk factors such as pregnancy'''
'''Imaging'''
* '''In patients with presumed uncomplicated pyelonephritis who will be managed as outpatients, initial radiologic evaluation can usually be deferred.'''
** However, if there is any reason to suspect a problem or if the patient will not have reasonable access to imaging if there should be no change in condition, renal US can rule out stones or obstruction.
* '''In patients with known or suspected complicated pyelonephritis, CT provides excellent assessment of the status of the urinary tract and the severity and extent of the infection.'''
*'''Renal US and CT are commonly used to evaluate patients initially for complicated UTIs or factors or to reevaluate patients who do not respond after 72 hours of therapy'''


===== Management =====
===== Management =====
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* '''Usually results from rupture of an acute cortical abscess into the perinephric space or from hematogenous seeding from sites of infection.'''
* '''Usually results from rupture of an acute cortical abscess into the perinephric space or from hematogenous seeding from sites of infection.'''
* Diabetes mellitus is present in ≈1/3rd of patients
* Diabetes mellitus is present in ≈1/3rd of patients
* '''Diagnosis and Evaluation'''
 
** '''The onset of symptoms is typically insidious. Symptoms are present for > 5 days in most patients'''
===== Diagnosis and Evaluation =====
** Perinephric abscess should be suspected in a patient with UTI and abdominal or flank mass or persistent fever after 4 days of antimicrobial therapy.
* '''The onset of symptoms is typically insidious. Symptoms are present for > 5 days in most patients'''
** '''Factors that differentiate perinephric abscess and acute pyelonephritis (2):'''
* Perinephric abscess should be suspected in a patient with UTI and abdominal or flank mass or persistent fever after 4 days of antimicrobial therapy.
**# '''Most patients with uncomplicated pyelonephritis are symptomatic for < 5 days before hospitalization, whereas most with perinephric abscesses are symptomatic for > 5 days'''
* '''Factors that differentiate perinephric abscess and acute pyelonephritis (2):'''
**# No patient with acute pyelonephritis remained febrile for longer than 4 days once appropriate antimicrobial agents were started. All patients with perinephric abscesses had a fever for at least 5 days, with a median of 7 days.
*# '''Most patients with uncomplicated pyelonephritis are symptomatic for < 5 days before hospitalization, whereas most with perinephric abscesses are symptomatic for > 5 days'''
* Management
*# No patient with acute pyelonephritis remained febrile for longer than 4 days once appropriate antimicrobial agents were started. All patients with perinephric abscesses had a fever for at least 5 days, with a median of 7 days.
** Antimicrobial agents should be immediately started upon diagnosis of perinephric abscess.
 
** '''For small perinephric abscesses (<3 cm), antibiotics alone can appropriately treat immune-competent patients'''
===== Management =====
** '''For larger collections or those not responsive to initial antibiotic therapy, intervention is the next step in treatment.'''
* Antimicrobial agents should be immediately started upon diagnosis of perinephric abscess.
*** '''Unlike in renal abscesses, early drainage of abscesses > 3 cm in diameter is recommended'''.
* '''<span style="color:#ff0000">For small perinephric abscesses (<3 cm), antibiotics alone can appropriately treat immune-competent patients'''
*** Once the perinephric abscess has been drained, the underlying problem must be dealt with.
* '''For larger collections or those not responsive to initial antibiotic therapy, intervention is the next step in treatment.'''
** '''<span style="color:#ff0000">Unlike in renal abscesses, early drainage of abscesses > 3 cm in diameter is recommended'''.
** Once the perinephric abscess has been drained, the underlying problem must be dealt with.


==== Chronic pyelonephritis ====
==== Chronic pyelonephritis ====
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== Questions ==
== Questions ==


# What is the mechanism of action of:
#
## TMP/SMX
## Nitrofurantoin
## Ciprofloxacin
## Ampicillin
## Fosfomycin
## Gentamicin
# Which antibiotics should be avoided in patients on warfarin?


== Answers ==
== Answers ==


# What is the mechanism of action of:
#
## TMP/SMX
## Nitrofurantoin
## Ciprofloxacin
## Ampicillin
## Fosfomycin
## Gentamicin
# Which antibiotics should be avoided in patients on warfarin?
## Fluoroquinolones
## TMP/SMX
## Metronidazole
## Ketoconazole (antifungal, not technically antibiotic)


== References ==
== References ==


* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 2, chap 12
* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 2, chap 12
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