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INFECTIONS & INFLAMMATION: URINARY TRACT INFECTIONS

• GU Antibiotic Regimens (WikiEM)
• Antibiotic sensitivities by species (WikiEM)

Definitions

• Cystitis: a clinical syndrome of dysuria, frequency, urgency, and occasionally suprapubic pain.
• These symptoms, although generally indicative of bacterial cystitis, may also be associated with infection of the urethra or vagina or non-infectious conditions such as interstitial cystitis, bladder carcinoma, or calculi.
• Conversely, patients may be asymptomatic and have infection of the bladder and possibly the upper urinary tract.
• Acute pyelonephritis: a clinical syndrome of chills, fever, and flank pain that is accompanied by bacteriuria and pyuria.
  • The term should not be used if flank pain is absent.
  • It may have no morphologic or functional components detectable by routine clinical modalities.
  • 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.
• 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
  • Complicated: infection associated with factors that increase the chance of acquiring bacteria and decrease the efficacy of therapy. Examples include (12):
    1. Male gender
    2. Pregnancy
    3. Elderly
    4. Diabetes
    5. Immunosuppression
    6. Functional or anatomic abnormality of urinary tract
    7. Indwelling urinary catheter
    8. Urinary tract instrumentation
    9. Recent antimicrobial agent use
    10. Hospital-acquired infection
    11. Childhood UTI
    12. Symptoms for > 7 days at presentation
• 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:
• First or isolated: infection that occurs in an individual who has never had a UTI or has one remote infection from a previous UTI.
• Unresolved: infection that has not responded to antimicrobial therapy and is documented to be the same organism with a similar resistance profile.
• Recurrent: infection that occurs after documented, successful resolution of an antecedent infection.
  • Subtypes (2):
    1. Bacterial re-infection: caused by re-introduction of bacteria into the urinary tract from outside
    2. Bacterial persistence: caused by the same bacteria re-emerging from a focus within the urinary tract, such as an infectious stone, source with prostate, or infrected atrophic kidney.
    • Relapse is frequently used interchangeably.
    • These definitions require careful clinical and bacteriologic assessment and are important because they influence the type and extent of the patient’s evaluation and treatment.
• Antimicrobial prophylaxis: prevention of re-infections of the urinary tract by the administration of antimicrobial drugs.
• Antimicrobial suppression: prevention of growth of a focus of bacterial persistence that cannot be eradicated.

Epidemiology

• UTIs are considered to be the most common bacterial infection
  • ≈30% of women will have had a symptomatic UTI requiring antimicrobial therapy by age 24
  • ≈50% of women will experience a UTI during their lifetime
• Catheter-associated UTIs (CAUTIs) are the most common nosocomial infection
  • 80% of nosocomial UTIs are secondary to an indwelling urethral catheter
• Once a patient has an infection, they are likely to develop subsequent infections.
  • The probability of recurrent UTIs increases with the number of previous infections and decreases in inverse proportion to the elapsed time between the first and the second infections.
  • Of these recurrent infections, ≈70% are caused by reinfection with different organisms, rather than recurrence with the same organism.
  • Most reinfections occur after 2 weeks and within 5 months
• The incidence of UTIs is increased in patients with spinal cord injuries, women with diabetes, multiple sclerosis, and HIV/AIDS
• An increased incidence of clinical asymptomatic and symptomatic UTIs appears to occur in women with diabetes mellitus, but there is no substantial increase among diabetic men.
• Although most UTIs in diabetic patients are asymptomatic, diabetes appears to predispose the patient to more severe infections.
• UTIs are 5x more prevalent in HIV-positive individuals than in control subjects
• Of all patients with bacteriuria, those with spinal cord injury have the most severe UTIs and related morbidity burden

Pathogenesis

• UTIs are a result of interactions between the uropathogen and the host. Successful infection of the urinary tract is determined in part by the:
  • Virulence factors of the bacteria
  • Inoculum size
  • Inadequacy of host defense mechanisms
• Routes of infection (3)
  1. Ascending (most common)
     • Most bacteria enter the urinary tract from the bowel via ascent through the urethra into the bladder.
       • Adherence of pathogens to the introital and urothelial mucosa plays a significant role in ascending infections.
       • This route is further enhanced in individuals with significant soilage of the perineum with feces, women who use spermicidal agents, and patients with intermittent or indwelling catheters.
     • Most episodes of pyelonephritis are caused by retrograde ascent of bacteria from the bladder through the ureter to the renal pelvis and parenchyma.
       • Although reflux of urine is probably not required for ascending infections, edema associated with cystitis may cause sufficient changes in the ureterovesical junction to permit reflux.
       • Once the bacteria are introduced into the ureter, they may ascend to the kidney unaided. However, ascent is increased by any process (endotoxins from Gram-negative bacteria, pregnancy, ureteral obstruction) that interferes with the normal ureteral peristaltic function
       • Bacteria that reach the renal pelvis can enter the renal parenchyma through the collecting ducts at the papillary tips and then ascend upward within the collecting tubules.
  2. Hematogenous
  • Uncommon in normal individuals; occasionally, the kidney is secondarily infected in patients with Staphylococcus aureus bacteremia originating from oral sites or with Candida fungemia
  3. Lymphatic route
• Direct extension of bacteria from the adjacent organs via lymphatics may occur in unusual circumstances, such as a severe bowel infection or retroperitoneal abscesses
• Urinary pathogens
• Most UTIs are caused by facultative anaerobes (organisms that are able to grow in both aerobic and anaerobic environments), usually originating from the bowel flora.
  • Uropathogens such as Staphylococcus epidermidis and Candida albicans originate from the flora of the vagina or perineal skin.
    • Note that staphylococci are gram-positive cocci in clusters, streptococci are gram-positive cocci in chains
• Common pathogens: KEEPPS (Klebsiella, E. Coli, Enterococcus, Proteus, Pseudomonas, Staph. Saprophyticus)
• Gram-negative:
• Enterobacteriaceae family
  1. E. coli (gram-negative bacilli)
     • Most common cause of UTIs
       • Accounts for 85% of community-acquired and 50% of hospital-acquired UTIs
     • E. coli sequence type ST131 (serotype O25b:H4) is a rapidly emerging cause of multidrug-resistant infections, including UTI; β-lactamases and fluoroquinolone resistance are common with this isolate
  2. Proteus (gram-negative bacilli)
  3. Klebsiella (gram-negative bacilli)
• Pseudomonadaceae family
  • Pseudomonas
• Gram-positive (responsible for the remainder of most community-acquired infections)
• Enteroccocus faecalis
• Staphylococcus saprophyticus
• Nosocomial infections are caused by E. coli, Klebsiella, Enterobacter (enterobacteriacea family), Citrobacter (enterobacteriacea family), Serratia, Pseudomonas, Providencia, E. faecalis, and S. epidermidis
• The prevalence of infecting organisms is influenced by the patient’s age.
  • S. saprophyticus causes ≈10% of symptomatic lower UTIs in young, sexually active females whereas it rarely causes infection in males and elderly individuals
  • Neonates and young infants should be covered for Enterococcus species when choosing empiric antibiotics since the incidence of infections with this uropathogen is higher in early infancy than at a later age.
• Fastidious organisms
• Obligatory anaerobes (organisms that die in the presence of oxygen)
• Clinically symptomatic UTIs in which only [obligatory] anaerobic organisms are cultured are rare
• Frequently found in suppurative infections of the genitourinary tract.
• The organisms found are usually:
  • Bacteroides species, including B. fragilis
  • Fusobacterium species
  • Anaerobic cocci
  • Clostridium perfringens
• Must be suspected when a patient with bladder irritative symptoms has cocci or gram-negative rods seen on microscopic examination of the centrifuged urine and routine quantitative aerobic cultures fail to grow organisms

• Mycobacterium TB and other non-TB mycobacteria

  • Mycobacterium tuberculosis and other nontuberculous mycobacteria do not grow under routine aerobic conditions and may be found during evaluation for sterile pyuria.
• Early events in uropathogenic E.Coli (UPEC) pathogenesis
  • UPEC expresses a number of adhesins that allow it to attach to urinary tract tissues. These adhesins are classified as either fimbrial or afimbrial
  • Type 1 (mannose-sensitive) pili are commonly expressed on both nonpathogenic and pathogenic E. coli.
  • “P” (“P” for pyelonephritis) pili, are found in most pyelonephritogenic strains of UPEC
• Epithelial cell receptivity
• Vaginal cells
• Women susceptible to UTI may have vaginal epithelial cells with increased adherence potential for pathogenic bacteria; this increased adherence in susceptible women is also shown in their buccal cells, suggesting a genetic trait for epithelial cell receptivity
• The presence or absence of blood group determinants on the surface of uroepithelial cells may influence an individual’s susceptibility to a UTI, further emphasizing the role of genetics in susceptibility to UTI
• Uropathogens attach more to epithelial cells in menopausal compared to pre-menopausal women; estrogen decreases the susceptibility to recurrent UTI
• Bladder cells
• FimH-mediated binding to the bladder epithelium is the initial step in the intricate cascade of events leading to UTIs
  • FimH is essential for UPEC invasion
• Natural defenses of the urinary tract
• Peri-urethral and urethral region
• The normal flora of the vaginal introitus, the peri-urethral area, and the urethra usually contain microorganisms that form a barrier against uropathogenic colonization, including (4):
  1. Lactobacilli
  2. Corynebacteria
  3. Coagulase-negative staphylococci
  4. Streptococci
• Urine
• The most inhibitory factors are (4):
  1. Osmolality
  2. Urea concentration
  3. Organic acid concentration
  4. pH
• Bacterial growth is inhibited by either very dilute urine or a high osmolality when associated with a low pH
• Uromodulin (Tamm-Horsfall protein), a kidney-derived protein may play a defensive role by saturating all the mannose-binding sites of the type 1 pili thus potentially blocking bacterial binding to the uroplakin receptors of the urothelium
• Bladder
• Immune response
• The host recognition of the pathogen is mediated by a series of pathogen-associated molecular pattern receptors (PAMPs), such as Toll-like receptors (TLRs), which provide the link between recognition of invading organisms and development of the innate immune response.
• The innate system response to an infection in the bladder or kidneys is primarily local inflammation.
• The innate immune response occurs more rapidly than the adaptive response and involves a variety of cell types, including polymorphonuclear leukocytes, neutrophils, macrophages, eosinophils, natural killer cells, mast cells, and dendritic cells.
• The innate response aids in establishing adaptive immunity because of interactions of macrophages, dendritic cells, and natural killer cells with T and B lymphocytes.
• Adaptive immunity involves the specific recognition of pathogens by T and B lymphocytes and production of high-affinity antibodies, a process that occurs 7-10 days after infection.
• UPEC enhances virulence by modulating inflammatory responses at the level of TLRs recognition, thereby extending a “window of opportunity” to establish infection by evading innate surveillance mechanisms.
• Alterations in host defense mechanisms
• Obstruction to urine flow is a key factor in increasing host susceptibility to UTI. Stasis also contributes to the growth of bacteria in the urine and their ability to adhere to the urothelial cells.
• Vesicoureteral reflux
  • Children with gross reflux and UTIs usually develop progressive renal damage manifested by renal scarring, proteinuria, and renal failure.
    • Those with a lesser degree of reflux usually improve or completely recover spontaneously or after treatment of the UTI.
  • In adults, the presence of reflux does not appear to decrease renal function unless there are stasis and concurrent UTIs.
• Renal papillary necrosis (RPN)
  • Defined as necrosis of papillae and inner portions of renal medulla (which receives 10% of renal blood flow).
  • Conditions associated with the development of renal papillary necrosis (POSTCARDS)§:
    1. Pyelonephritis
    2. Obstruction of the urinary tract
    3. Sickle cell disease
    4. Tuberculosis
    5. Cirrhosis
    6. Analgesic abuse
    7. Renal vein thrombosis
    8. Diabetes mellitus (most common§)
    9. Systemic vasculitis
    • Miscellaneous: cryoglobulinemia, renal candidiasis, contrast media injection, amyloidosis, calyceal arteritis, necrotizing angiitis, rapidly progressive glomerulonephritis, hypotensive shock, acute pancreatitis, renal transplant rejection, dehydration, hypoxia, and jaundice of infants
    • The role of infection in the development and progression of renal papillary necrosis is controversial.
  • Early diagnosis is important to improve prognosis and reduce morbidity.
  • Acute ureteral obstruction caused by a sloughed papilla with concomitant UTI is a urologic emergency

Natural history

• The long-term effects of
• Complicated UTIs can lead to progressive renal damage
• Uncomplicated recurrent UTIs are not completely known
  • No association between recurrent uncomplicated UTIs and renal scarring, hypertension, or progressive renal azotemia has been established
• 57-80% of bacteriuric women who are untreated or treated with placebo clear their infections spontaneously.
• Whether a patient receives no treatment at all or short-term, long-term, or prophylactic antimicrobial treatment, the risk of recurrent bacteriuria remains the same
  • Prophylactic antimicrobial therapy reduces re-infections but does not alter the underlying predisposition to recurring infection.
    • Patients with frequent UTI who take prophylactic antimicrobial agents for extended periods (≥6 months) may decrease their infections during the time of prophylaxis, but the rate of infection returns to the pretreatment rate after prophylaxis is stopped

Diagnosis and Evaluation

• History and physical exam
• Cystitis
• Usually associated with dysuria, frequency, and/or urgency. Suprapubic pain and hematuria are less common.
• Lower tract symptoms usually predate the appearance of upper tract symptoms by several days.
• Pyelonephritis
• Classically associated with fever, chills, and flank pain. Nausea and vomiting may be present.
• Renal or perirenal abscess
• May cause indolent fever and flank mass and tenderness.
  • In the elderly, the symptoms may be much more subtle (e.g., epigastric or abdominal discomfort) or the patient may be asymptomatic.
• Indwelling catheters
• Often have asymptomatic bacteriuria, but fever associated with bacteremia may occur rapidly and become life threatening.
• Laboratory
• Urine collection
• Voided and catheterized specimens
• Males
• 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.
• The first 10 mL of urine (representative of the urethra) and a midstream specimen (representative of the bladder) should be obtained.
• 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.
• Catheterization of a male patient for urine culture is not indicated unless the patient cannot urinate.
• Females
• 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.
  • Cleansing with antiseptics is not recommended because they may contaminate the voided specimen and provide a false-negative urine culture.
• The voided specimen is contaminated if it shows evidence of vaginal epithelial cells and lactobacilli on urinalysis, and a catheterized specimen should be collected.
• Suprapubic aspiration
• Advantage: highly accurate
• Disadvantages: some morbidity
• Limited clinical usefulness except for a patient who cannot urinate on command such as patients with spinal cord injuries and newborns
• Steps to perform procedure available in CW11 page 250
• Bag specimens
  • Unreliable and unacceptable for diagnosis of UTI in high-risk populations and infants.
    • 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.
      • 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.
• Urinalysis (UA)
• Provides rapid identification of bacteria and WBCs and presumptive diagnosis of UTI
• Assess for bacteria, epithelial cells, pyuria, hematuria, nitrites
• Diagnosis is confirmed by urine culture
  • UA does not replace urine culture and may be more relevant for screening in asymptomatic patients
• Usually, the sediment from an ≈5-10-mL specimen obtained by centrifugation for 5 minutes at 2000 rpm is analyzed.
• Bacteriuria
• Definition of bacteriuria: presence of bacteria in the urine, which is normally free of bacteria
• 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.
• Can be symptomatic or asymptomatic
• Found in > 90% of infections with counts of ≥10⁵ colony-forming units (cfu) per milliliter of urine and is a highly specific finding.
  • Bacteria are usually not detectable microscopically with lower cfu (10^2-10⁴/mL).
• Causes of false-negative UA and culture:
  1. Early in an infection
  2. In context of increased fluid intake and subsequent dilute urine
  • A negative urinalysis for bacteria never excludes the presence of bacteria
• Causes of false-positive UA and culture:
  1. Contamination of an abacteriuric specimen during collection
     • Contamination can be considered if numerous squamous epithelial cells (indicative of preputial, vaginal, or urethral contaminants) are present
       • The possibility of contamination increases as the reliability of the collection technique decreases from suprapubic aspiration to catheterization to voided specimens
• Pyuria
  • 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 absence of pyuria should cause the diagnosis of UTI to be questioned until urine culture results are available.
• Bacteriuria without pyuria is generally indicative of bacterial colonization without infection of the urinary tract.
• Sterile pyuria (pyruria without bacteriuria) warrants evaluation for tuberculosis, stones, or cancer. Many other causes§
  • Almost any injury to the urinary tract, from chlamydial urethritis to glomerulonephritis and interstitial cystitis, can elicit large numbers of fresh polymorphonuclear leukocytes
• Tests for detecting pyuria by determining leukocyte esterase activity have been developed
• Nitrites
• Bacteria may convert urinary nitrates into nitrites and this may be used as evidence of UTI.
• 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.
• One very important gram-negative exception is Pseudomonas, which does not contain the enzymatic machinery to convert nitrates to nitrites
• Hematuria
• Indicator of an inflammatory response
• Microscopic hematuria is found in 40-60% of cases of cystitis and is uncommon in other dysuric syndromes
• Urine culture
• Techniques available (2): direct surface plating and dip slides
• 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]
• 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.
• The ≥10⁵ cut-off may also lead to overdiagnosis in patients with contaminated urine.
• 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
• Not required in most cases of UTI because clinical and laboratory findings alone are sufficient for correct diagnosis and adequate management of most patients.
• Indications for imaging (8):
  1. Risk factors for complicated UTI (see above)
  2. Febrile infections
  3. Failure to respond to appropriate therapy
  4. Potential obstruction (e.g., ureteral stricture, tumor, history of genitourinary surgery that predisposes to obstruction, such as ureteral reimplantation or ureteral diversion, history of calculi, especially infection (struvite) stones, signs and symptoms of obstruction)
  5. Potential papillary necrosis (recall risk factors for renal papillary necrosis above)
  6. Polycystic kidneys in patients in dialysis or with severe renal insufficiency
  7. Neurogenic bladder
  8. 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

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
    • 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
      • In patients with renal insufficiency, dosage modifications are necessary for antibiotics that are renally cleared, including:
        1. Ciprofloxacin
        2. Nitrofurantoin
        3. Trimethoprim/sulfamethoxazole
        4. Trimethoprim
        5. Amoxicillin
        6. Piperacillin/tazobactam
        7. Cephalexin
        8. Cefuroxime
        9. Levofloxacin
        10. Clarithromycin
        11. 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)
        1. Inherited chromosomal-mediated
        2. Acquired chromosomal
        3. 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

Drug or drug class	Mechanism of action	Mechanisms of drug resistance
β-Lactams (penicillins, cephalosporins, carbapenems, aztreonam)	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)
Vancomycin	Inhibits bacterial cell wall synthesis	Enzymatic alteration of peptidoglycan at different point than target
Fosfomycin	Inhibits bacterial cell wall synthesis	Novel amino acid substitutions or the loss of function of transporters
Aminoglycosides (gentamicin, tobramycin, etc.)	Inhibits ribosomal protein synthesis	Downregulation of drug uptake into bacteria Bacterial production of aminoglycoside-modifying enzymes
Clindamycin, macrolides (erythromycin, clarithromycin, azithromycin)	Inhibits ribosomal protein synthesis
Quinolones (ciprofloxacin, levofloxacin, etc.)	Inhibits bacterial DNA gyrase	Mutation in DNA gyrase-binding site Changes in cell wall porin size (decreased penetration) Active efflux
Trimethoprim-sulfamethoxazole	Competitive inhibition of dihydrofolate reductase	Draws folate from environment (enterococci)
Nitrofurantoin	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

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

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 with methicillin)
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 sodium loading
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 auditory components 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 and nephrotoxic drugs.
Fluoroquinolones	Photosensitivity Mild GI effects Central nervous system effects, including dizziness, tremors, confusion, mood disorder, hallucinations, light-headedness Tendon rupture (incidence 20 cases/100,000), should be discontinued at the first sign of tendon pain 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 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 use dramatically 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	GI upset Peripheral polyneuropathy (especially in patients with impaired renal function, anemia, diabetes, electrolyte imbalance, vitamin B deficiency, and debilitated) Hemolysis in patients with G6PD deficiency Pulmonary hypersensitivity reactions can range from acute to chronic and include cough, dyspnea, fever, and interstitial changes [e.g. fibrosis]. Hepatoxicity	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 and nephrotoxic drugs.

 

• 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
  • TMP-SMX should be avoided during pregnancy because of early potential for teratogenicity and late potential for kernicterus
  • 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.
  • 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

• Risk factors for bladder UTI
• Reduced urine flow
• Outflow obstruction (BPH, prostate cancer, urethral stricture, foreign body (calculus))
• Neurogenic bladder
• Inadequate fluid uptake (dehydration)
• Promote colonization
• Sexual activity—increased inoculation
• Spermicide—increased binding
• Estrogen depletion—increased binding
• Antibiotic use—decreased indigenous flora
• Facilitate ascent
• Catheterization
• Urinary incontinence
• Fecal incontinence
• Residual urine with ischemia of bladder wall
• Uncomplicated cystitis
• Pathophysiology
• Pathogens
  • E. coli is the causative organism in 75-90% of cases of acute cystitis in young women.
  • S. saprophyticus, a commensal organism of the skin, is the second most common cause of acute cystitis in young women, accounting for 10-20% of these infections. Other organisms less commonly involved include Klebsiella and Proteus species and Enterococcus.
  • In men, E. coli and other Enterobacteriaceae are the most commonly identified organisms.
• Sexual transmission of uropathogens has been suggested by demonstrating identical E. coli in the bowel and urinary flora of sex partners
• Diagnosis and Evaluation
• History and Physical Exam
  • History
    • Variable presenting symptoms of cystitis but usually include dysuria, frequency, and/or urgency. Suprapubic pain, hematuria, or foul-smelling urine may develop.
    • By definition, acute cystitis is a superficial infection of the bladder mucosa, so fever, chills, and other signs of dissemination are not present.
    • Cystitis must be differentiated from other inflammatory infectious conditions in which dysuria may be the most prominent symptom, including:
      • Vaginitis
      • Urethral infections caused by sexually transmitted pathogens
      • Miscellaneous non-inflammatory causes of urethral discomfort
  • Physical exam
    • Some patients may experience suprapubic tenderness, but most have no diagnostic physical findings.
    • In females, physical examination should include the possibility of vaginitis, herpes, and urethral pathology, such as a diverticulum.
• Laboratory
• Urinalysis
• The presumptive laboratory diagnosis of acute cystitis is based on microscopic urinalysis, which indicates microscopic pyuria, bacteriuria, and occasionally hematuria.
• Urine culture
• Remains the definitive test
  • In symptomatic patients, presence of ≥10² cfu/mL bacteria usually indicates infection
• Management
• ≈90% of women are asymptomatic within 72 hours after initiating antibiotics
• A follow-up visit or culture is not required in young women who are asymptomatic after therapy.
• A follow-up visit, urinalysis, and urine culture are recommended in older women or those with potential risk factors and in men.
• Urologic evaluation is unnecessary in women and is usually unnecessary in young men who respond to therapy.  However, UTIs in most men should be considered complicated until proven otherwise.
• If a patient does not respond to therapy, appropriate microbiologic and urologic evaluations should be undertaken for the causes of unresolved and complicated UTIs.
• See CW11 Table 12-10 for Treatment Regimens for Acute Cystitis

• Asymptomatic bacteriuria
• Screening for or treatment of asymptomatic bacteriuria is not appropriate and should be discouraged
  • Exceptions (populations in whom treatment has been documented to be beneficial)
    • Pregnant females
    • Patients undergoing urologic interventions
    • Candiduria in neonates (not technically a "bacter"uria")
      • Treat candiduria in neonates with parenteral fluconazole
• Complicated cystitis
• Complicated UTIs are those that occur in a patient with a compromised urinary tract (see list above) or that are caused by a very resistant pathogen
• Urine cultures are mandatory to identify the bacteria and its antibiotic susceptibility
• While uncomplicated cystitis in a young sexually active male may not require investigation beyond a follow-up urine culture, a complicated UTI in an older male warrants urologic evaluation such as CT urogram and cystoscopy due to the high incidence of associated urologic abnormalities such as obstruction from either urethral or ureteral strictures, tumor, or stones.
  • ≈50% of males with UTIs have a significant abnormality
• Management: See CW11 Table 12-13

• Unresolved UTIs
• Indicates that initial therapy has been inadequate in eliminating symptoms and/or bacterial growth in the urinary tract.
• If the symptoms of UTI do not resolve by the end of treatment or if symptoms recur shortly after therapy, urinalysis and urine culture with susceptibility testing should be obtained.
  • If the patient’s symptoms are significant, empirical therapy with a fluoroquinolone is appropriate, pending results of the culture and susceptibility testing.
• Causes of Unresolved Bacteriuria, in Descending Order of Importance
  1. Pre-existing bacterial resistance to the drug selected for treatment
  2. Development of resistance from initially susceptible bacteria
  3. Bacteriuria caused by 2 different bacterial species with mutually exclusive susceptibilities
  4. Rapid re-infection with a new, resistant species during initial therapy for the original susceptible organism
  5. Renal failure (inability to deliver an adequate concentration of antibiotics into the urinary tract)
  6. Papillary necrosis from analgesic abuse (defects in the medullary concentrating ability dilutes the antibiotic)
  7. Staghorn calculi (large mass of bacteria)
  8. Self-inflicted infections or deception in taking antimicrobial drugs (a variant of Munchausen syndrome)
• The first 4 causes that are associated with resistant bacteria require no further evaluation. However, if re-culture shows that the bacteria are sensitive to the antimicrobial agent the patient is taking, renal function and radiologic evaluation should be performed to identify renal or urinary tract abnormalities.
• Management
  • Initial empirical antimicrobial selection for unresolved UTI should be based on the assumption that the bacteria are resistant and an antibiotic different from the original agent should be selected.
    • Fluoroquinolones offer excellent coverage in most cases and should be given for 7 days.
  • When the bacterial susceptibilities are available, adjustments can be made if necessary.
  • Urine cultures should be performed during and 7 days after therapy to ensure microbiologic efficacy.
• Recurrent UTI
• See AUA/CUA Guideline Notes
• Recurrent UTIs are caused by either re-emergence of bacteria from a site within the urinary tract (bacterial persistence) or new infections from bacteria outside the urinary tract (re-infection).
• Clinical identification of these two types of recurrence is based on the pattern of recurrent infections. Bacterial persistence must be caused by the same organism in each instance, and infections that occur at close intervals are characteristic. Conversely, reinfections usually occur at varying and sometimes long intervals and often are caused by different species.
• The distinction between bacterial persistence and reinfection is important in management because patients with bacterial persistence can usually be cured of the recurrent infections by identification and surgical removal or correction of the focus of infection. Conversely, women with reinfection usually do not have an alterable urologic abnormality and require long-term medical management.
• The probability of recurrent UTIs
  • Increases with the number of previous infections
  • Decreases in inverse proportion to the elapsed time between the first and the second infections
• Bacterial persistence
• Once the bacteriuria has resolved (i.e., the urine shows no growth for several days after the antimicrobial agent has been stopped), recurrence with the same organism can arise from a site within the urinary tract that was excluded from the high urine concentrations of the antimicrobial agent.
• Correctable urologic abnormalities that cause bacteria to persist within the urinary tract between episodes of recurrent bacteriuria:
  1. Infection stones
  2. Chronic bacterial prostatitis
  3. Foreign bodies
  4. Urethral diverticula and infected periurethral glands
  5. Unilateral infected atrophic kidney
  6. Ureteral duplication and ectopic ureters
  7. Unilateral medullary sponge kidney
  8. Non-refluxing, normal-appearing, infected ureteral stumps after nephrectomy
  9. Infected urachal cysts
  10. Infected communicating cysts of the renal calyces
  11. Papillary necrosis
  12. Perivesical abscess with fistula to bladder
• Re-infections
• Patients with recurrent infections caused by different species or occurring at long intervals almost invariably have reinfections. These reinfections most often occur in females and are associated with ascending colonization from the bowel flora. Reinfections in men are often associated with a urinary tract abnormality.
• The possibility of a vesicoenteric or vesicovaginal fistula should be considered when the patient has any history of pneumaturia, fecaluria, diverticulitis, obstipation, previous pelvic surgery, or radiation therapy.
• Evaluation for presumed reinfections must be individualized.
• Pyocystis
• Occurs in ≈20% of patients who undergo supravesical diversion
• Patients typically have a malodorous discharge and may develop sepsis
• Management
  • Conservative: routine bladder irrigations
  • If conservative measures fail, vaginal vesicostomy (creation of a large vesico-vaginal fistula), is an effective method of preventing pyocystis in females.
• Urachal cyst infection
  • The cyst material consists of desquamated epithelial cells. These cells can become infected
  • Staphylococcus aureus has been identified as the most common organism.

Kidney infections

• Bacterial nephritis
• Although the classic symptoms of acute onset of fever, chills, and flank pain are usually indicative of renal infection, some patients with these symptoms do not have renal infection. Conversely, significant renal infection may be associated with an insidious onset of nonspecific local or systemic symptoms, or it may be entirely asymptomatic.
• The relationship between laboratory findings and the presence of renal infection often is poor.
  • The presence of bacteriuria and pyuria, the hallmarks of UTI, are not predictive of renal infection.
  • Conversely, patients with significant renal infection may have sterile urine if the ureter draining the kidney is obstructed or the infection is outside of the collecting system.
  • The pathologic and radiologic criteria for diagnosing renal infection may also be misleading.
• The effect of renal infection on renal function is varied.
  • Acute or chronic pyelonephritis may transiently or permanently alter renal function, but non-obstructive pyelonephritis is no longer recognized as a major cause of renal failure.
    • 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
• Pathogens
  • E. coli (80% of cases) constitutes a unique subgroup that possesses special virulence factors
  • 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.
• Diagnosis and Evaluation
• History and physical exam
• The clinical spectrum ranges from gram-negative sepsis to cystitis with mild flank pain.
• 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
• Differential diagnoses: acute appendicitis, diverticulitis, and pancreatitis can cause a similar degree of pain, but the location of the pain often is different
• On physical examination, there often is tenderness to deep palpation in the costovertebral angle
• Laboratory
• CBC
  • May have leukocytosis with a predominance of neutrophils.
• Urinalysis
  • Usually reveals numerous WBCs, often in clumps, and bacterial rods or chains of cocci.
  • The presence of large amounts of granular or leukocyte casts in the urinary sediment is suggestive of acute pyelonephritis.
• Urine cultures
  • Usually positive
    • ≈20% of patients have urine cultures with < 10⁵ cfu/mL and therefore negative results on Gram staining of the urine
• Blood cultures
  • 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
• 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
• 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.
• Management
• For patients with community-acquired infections who will be managed as outpatients, single-drug oral therapy with a fluoroquinolone is more effective than TMP-SMX.
• Many physicians administer a single parenteral dose of an antimicrobial agent (ceftriaxone, gentamicin, or a fluoroquinolone) before initiating oral therapy.
• If a gram-positive organism is suspected, amoxicillin or amoxicillin/clavulanic acid is recommended
• If a patient has an uncomplicated infection but is sufficiently ill to require hospitalization (high fever, high WBC count, vomiting, dehydration, evidence of sepsis), has complicated pyelonephritis, or fails to improve during the initial outpatient treatment period, a parenteral fluoroquinolone, an aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside is recommended.
• If gram-positive cocci are causative, ampicillin/sulbactam with or without an aminoglycoside is recommended.
• See CW11 Table 12-15

• An obstructed kidney has difficulty concentrating and excreting antimicrobial agents. Any substantial obstruction must be relieved expediently by the safest and simplest means.
• Repeat urine cultures should be performed after 5-7 days of therapy and 10-14 days after discontinuing antimicrobial therapy to ensure that the urinary tract remains free of infections.
  • 10-30% of individuals with acute pyelonephritis relapse after a 14-day course of therapy.
  • Patients who relapse usually are cured by a second 14-day course of therapy, but occasionally a 6-week course is necessary
• Acute focal and multifocal bacterial pyelonephritis
• Also known as lobar nephronia
• An uncommon, severe form of acute renal infection in which a heavy leukocyte infiltrate is confined to a single renal lobe (focal) or multiple lobes (multifocal).
• Represents a midpoint on the spectrum between pyelonephritis and renal abscess
• Clinical presentation is similar to that of patients with acute pyelonephritis but usually is more severe
• ≈50% of patients are diabetic, and sepsis is common
• The diagnosis must be made by radiologic examination (US or CT)
• Management
  • Includes hydration and IV antimicrobial agents for at least 7 days, followed by 7 days of oral antimicrobial therapy
    • Failure to respond to antimicrobial therapy is an indication for appropriate studies to rule out obstructive uropathy, renal or perirenal abscess, renal carcinoma, or acute renal vein thrombosis
• Renal Abscess
• A collection of purulent material confined to the renal parenchyma
• Pathogens
  • Majority caused by gram-negative organisms
• Pathogenesis
  • Ascending infection associated with tubular obstruction from prior infections or calculi appears to be the primary pathway for the establishment of gram-negative abscesses.
• Diagnosis and Evaluation
  • May present with fever, chills, abdominal or flank pain, and occasionally weight loss and malaise. The patient typically has marked leukocytosis.
  • CT is the diagnostic procedure of choice because it provides excellent delineation of the tissue.
  • CT- or US-guided needle aspiration may be necessary to differentiate an abscess from a hypervascular tumor.
• Management
• Size <3-5cm: IV antibiotics are appropriate ina clinically stable patient
  • Antibiotics, if begun early enough in the course of the process, may obviate surgical procedures.
• Size≥5 cm: percutaneous drainage
• Patients should have serial examinations with US or CT until the abscess resolves
• Perinephric abscess
• 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
• Diagnosis and Evaluation
  • The onset of symptoms is typically insidious. Symptoms are present for > 5 days in most patients
  • Perinephric abscess should be suspected in a patient with UTI and abdominal or flank mass or persistent fever after 4 days of antimicrobial therapy.
  • Factors that differentiate perinephric abscess and acute pyelonephritis (2):
    1. Most patients with uncomplicated pyelonephritis are symptomatic for < 5 days before hospitalization, whereas most with perinephric abscesses are symptomatic for > 5 days
    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.
• Management
  • 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
  • For larger collections or those not responsive to initial antibiotic therapy, intervention is the next step in treatment.
    • 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
• In patients without underlying renal or urinary tract disease, chronic pyelonephritis secondary to UTI is a rare disease and an even more rare cause of chronic renal failure. In patients with underlying functional or structural urinary tract abnormalities, however, chronic renal infection can cause significant renal impairment.
• Diagnosis and Evaluation
  • There are no symptoms of chronic pyelonephritis until it produces renal insufficiency, and then the symptoms are similar to those of any other form of chronic renal failure
  • Similarly, urinary findings and the presence of renal infection correlate poorly. Bacteriuria and pyuria, the hallmarks of UTI, are not predictive of renal infection
  • Imaging findings:
    1. Asymmetry and irregularity of the kidney outlines
    2. Blunting and dilation of ≥1 calyces
    3. Cortical scars at the corresponding site
• Management of radiographic evidence of pyelonephritis should be directed at treating infection if present, preventing future infections, and monitoring and preserving renal function
• Infected Hydronephrosis and Pyonephrosis
• Infected hydronephrosis is bacterial infection in a hydronephrotic kidney.
• Pyonephrosis is infected hydronephrosis associated with suppurative destruction of the parenchyma of the kidney, in which there is total or nearly total loss of renal function
• The patient is usually very ill, with high fever, chills, flank pain, and tenderness.
• A previous history of urinary tract calculi, infection, or surgery is common
• Emphysematous pyelonephritis
• An acute necrotizing parenchymal and peri-renal infection caused by gas-forming uropathogens
• Pathogens
• E. coli is the most common cause of emphysematous pyelonephritis and emphysematous cystitis
• Usually occurs in diabetic patients
• Diagnosis and Evaluation
  • Almost all patients display the classic triad of fever, vomiting, and flank pain
  • Imaging
    • The diagnosis is established radiographically by the presence of gas in the parenchyma or collecting system.
      • A crescentic collection of gas over the upper pole of the kidney is more distinctive.
      • As the infection progresses, gas extends to the perinephric space and retroperitoneum.
      • This distribution of gas should not be confused with cases of emphysematous pyelitis in which air is in the collecting system of the kidney. Emphysematous pyelitis is secondary to a gas-forming bacterial UTI, often occurs in non-diabetic patients, is less serious, and usually responds to antimicrobial therapy.
• Management
  • Requires urgent management.
    • Most patients are septic, and fluid resuscitation and broad-spectrum antimicrobial therapy are essential.
• If a kidney is obstructed, urinary diversion (stent or nephrostomy) must be instituted
• If the kidney is functioning, medical therapy can be considered.
• Indications for nephrectomy (2):
  1. Affected kidney is non-functioning and not obstructed because medical treatment alone is usually lethal
  2. Failure to improve after a few days of therapy
• Infectious Granulomatous Nephritis

• Xanthogranulomatous pyelonephritis (XGP)
• Epidemiology
• Rare
• Women are more commonly affected than men
• Diabetics at increased risk
• Pathophysiology
• Severe, chronic renal infection typically resulting in diffuse renal destruction
• Begins within the pelvis and calyces and subsequently extends into and destroys renal parenchymal and adjacent tissues
• Primary factors involved in the pathogenesis of XGP (3):
  1. Nephrolithiasis (usually staghorn)
  2. Obstruction
  3. Infection
• Pathogens
  • Proteus is the most common organism involved with XGP
  • E. coli is also common
• Diagnosis and Evaluation
• Most cases are unilateral and result in a non-functioning, enlarged kidney associated with obstructive uropathy secondary to nephrolithiasis.
• The infecting organism may be revealed only by tissue cultures obtained during surgery.
  • ≈10% of patients have mixed cultures.
  • ≈1/3rd of patients have no growth in their urine, probably because many patients have recently taken or are taking antibiotics when cultures are obtained.
• Urinalysis usually shows pus and protein
• Imaging
• CT
  • Most useful modality
• Usually demonstrates a large, reniform mass with the renal pelvis tightly surrounding a central calcification but without pelvic dilatation
  • Appears similar to virtually every other inflammatory disease of the kidney, as well as renal cell carcinoma; often cannot be used to differentiate between XGP and renal cell carcinoma
  • 50-80% of patients show the classic triad of
    1. Unilateral renal enlargement
    2. With little or no function
    3. and a large calculus in the renal pelvis.
• Pathology
• Characterized by accumulation of lipid-laden foamy macrophages
• Management
• Antibiotics
  • May be necessary to stabilize the patient pre-peratively,
  • Occasionally, long-term antibiotics therapy will eradicate the infection and restore renal function.
• Nephrectomy
  • Because the renal abnormality may be diagnosed preoperatively as a renal tumor and/or is diffuse, nephrectomy is usually performed.
  • If localized XGP is diagnosed preoperatively or at exploration, it is amenable to partial nephrectomy
• Malacoplakia
• Means “soft plaque” in Greek
• Pathogenesis
  • Probably results from abnormal macrophage function in response to a bacterial infection, which is most often E. coli.
• Diagnosis and Evaluation
  • Should be considered when one or more renal masses are observed, particularly in female patients with recurrent UTIs with E. coli, altered immune response syndromes, or cystoscopic evidence of malacoplakia or filling defects in the collecting system
  • Biopsy demonstrates von Hansemann cells and Michaelis-Gutmann bodies which are pathognomonic
• Management
  • Should be directed at control of the UTIs, which should stabilize the disease process.
  • Long-term antibiotics (sulfonamides, rifampin, doxycycline, and TMP) are effective
• Renal echinococcosis
• Parasitic infection caused by the larval stage of the tapeworm Echinococcus granulosus.
• Diagnosis and Evaluation
  • Symptoms are those of a slowly growing tumor.
  • Most patients are asymptomatic or have a flank mass, dull pain, or hematuria.
  • Because the cyst is focal, it rarely affects renal function.
  • Rarely, the cyst ruptures into the collecting system, and may be associated severe colic and passage of debris resembling grape skins in the urine (hydatiduria).
  • Excretory urography typically shows a thick-walled cystic mass, occasionally calcified
  • Diagnostic aspiration should not be performed because of the danger of rupture and spillage of the highly antigenic cyst contents and risk of fatal anaphylaxis
• Management
  • Surgery remains the mainstay of treatment

Bacteremia, sepsis, and septic shock

• Definitions:
• Systemic inflammatory response syndrome (SIRS): a clinical syndrome characterized by extremes of body temperature, heart rate, ventilation, and immune response.
  • SIRS can occur in response to multiple insults, including systemic infection, trauma, thermal injury, or a sterile inflammation.
• Sepsis: SIRS + infection (either documented or strongly suspected)
• Severe sepsis: sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion, typically systolic blood pressure (SBP) <90 mm Hg or mean arterial pressure (MAP) <70 mm Hg
• Septic shock: an extreme form of sepsis with sepsis-induced hypotension persisting despite adequate fluid resuscitation; findings may include elevated lactic acid or oliguria
• Earliest metabolic change in septicemia is respiratory alkalosis
  • Even before temperature extremes and the onset of chills, bacteremic patients often begin to hyperventilate, resulting in respiratory alkalosis
• In classic studies of sepsis syndrome and septic shock, gram-negative bacteria were predominant organisms isolated in 30-80% of cases and gram-positive bacteria in 5-24%.
  • Anaerobic organisms may cause bacteremia when the source is a postsurgical intra-abdominal abscess or transrectal prostatic biopsy.
  • The prime initiator of gram-negative bacterial septic shock is endotoxin, an LPS component of the bacterial outer membrane.
    • The exotoxins produced by some bacteria can initiate septic shock. However, the bacteria themselves, and in particular their cell wall components, are primarily responsible for the development of septic shock.
• Clinical factors have been predictive of the subsequent isolation of a resistant pathogen:
  • Use of an antimicrobial drug in the last month
  • Advanced age
  • Male sex
• The principles of management of sepsis include resuscitation, supportive care, monitoring, administration of broad-spectrum antimicrobial agents, and drainage or elimination of infection

Bacteruria in the elderly

• Epidemiology
  • > 20% of women and 10% of men age > 65 have bacteriuria
• Pathogenesis
  • Age-related changes related to increased risk of bacteruria include:
    1. Decline in cell-mediated immunity
    2. Neurogenic bladder dysfunction
    3. Increased perineal soiling as a result of fecal and urinary incontinence
    4. Increased incidence of urethral catheter placement
    5. In women, changes in the vaginal environment associated with estrogen depletion
• Pathogens
  • E. coli remains the most common uropathogen, causing 75% of these infections.
  • S. saprophyticus is not seen in this population.
• Diagnosis and Evaluation
  • Diagnosis of bacteriuria and UTIs in the elderly can be difficult.
  • Most elderly patients with bacteriuria are asymptomatic
  • Urinary tract symptoms are often absent, and concomitant disease can mask or mimic UTI. Even severe upper tract infections may not be associated with fever or leukocytosis
  • Screening for asymptomatic bacteriuria in elderly residents in the community or long-term care facilities is not recommended.
    • In RCTs of antimicrobial vs. no therapy in elderly male and female nursing home residents with asymptomatic bacteriuria, no decrease in symptomatic episodes and no improvement in survival. In fact, treatment with antimicrobial therapy increases the occurrence of adverse drug effects and reinfection with resistant organisms and increases the cost of treatment.
• Management
  • Asymptomatic
    • Not recommended
    • The treatment of asymptomatic bacteriuria to improve incontinence has not been justified
  • Symptomatic
    • For elderly patients with symptomatic UTI, 7 days of therapy is recommended.
      • The goal in this population is to eliminate symptoms but not sterilize the urine
  • Other scenarios
    • Bacteriuria that leads to UTIs in elderly in the presence of underlying structural urinary tract abnormalities (e.g., obstruction with hydronephrosis) or systemic conditions (e.g., severe diabetes mellitus) are clinically significant, can lead to renal failure, and require prompt therapy.
    • UTIs caused by urea-splitting bacteria, such as Proteus or Klebsiella species that cause formation of infection stones, may also lead to severe renal damage.
      • Urea in the urine is split into large amounts of ammonia by urea-splitting bacteria which is absorbed systemically and may result in encephalopathy or even coma at high levels, particularly in obstruction

Catheter-associated bacteriuria

• Epidemiology
  • Most common nosocomial infection
    • 80% of nosocomial UTIs are secondary to an indwelling urethral catheter
• Pathogenesis
  • Closed drainage is the most effective measure at reducing catheter-associated UTI
• Diagnosis and Evaluation
  • Most patients are asymptomatic
• Management
  • Patients with indwelling catheters should be treated only if they become symptomatic (e.g., febrile).
    • Urine cultures should be performed before initiating antimicrobial therapy.
    • The antimicrobial agent should be discontinued within 48 hours of resolution of the infection.
    • If the catheter has been indwelling for several weeks, encrustation may shelter bacteria from the antimicrobial agent; therefore the catheter should be changed. [Unclear but likely does not need to be changed if asymptomatic]

UTIs in patients with spinal-cord injury (SCI)

• Pathogenesis
  • Risk factors include impaired voiding, overdistention of the bladder, elevated intravesical pressure, increased risk of urinary obstruction, vesicoureteral reflux, instrumentation, increased incidence of stones, decreased fluid intake, poor hygiene, perineal colonization, decubiti, and other evidence of local tissue trauma, and reduced host defense associated with chronic illness
• Pathogens
  • Most bacteriuria in short-term catheterization is of a single organism, whereas patients catheterized for longer than a month will usually demonstrate a polymicrobial flora caused by a wide range of gram-negative and gram-positive bacterial species
• Diagnosis and Evaluation
  • The majority of patients with SCI with bacteriuria are asymptomatic. Because of a loss of sensation, patients usually do not experience frequency, urgency, or dysuria. More often, they complain of flank, back, or abdominal discomfort, leakage between catheterizations, increased spasticity, malaise, lethargy, and/or cloudy, malodorous urine.
  • UTI is the most common cause of fever in the SCI patient
• Managment
  • CIC has been shown to decrease lower urinarcy tract complications by maintaining low intravesical pressure and reducing the incidence of stones. CIC also appears to reduce complications associated with an indwelling catheter, such as UTI, fever, bacteremia, and local infections such as epididymitis and prostatitis.
    • Suprapubic catheters and indwelling urethral catheters eventually have an equivalent infection rate. However, the onset of bacteriuria may be delayed using a suprapubic catheter compared with a urethral catheter (different than NLUTD guidelines which suggest decreased infection rate with suprapubic compared to indwelling)
  • In the absence of vesicoureteral reflux, asymptomatic bacteruria in patients managed with clean intermittent catheterization is not a significant risk factor for renal damage and does not require antibiotic therapy.
  • Only symptomatic patients require therapy.
    • Because of the diverse flora and high probability of bacterial resistance, a urine culture must be obtained before initiating empirical therapy.
    • For afebrile patients, an oral fluoroquinolone is the agent of choice.
  • An indwelling catheter should be changed to ensure maximal drainage and eliminate bacterial foci in catheter encrustations.
  • Antimicrobial prophylaxis is not supported for most patients who have neurogenic bladder caused by spinal cord injury

Periurethral abscess

• Life-threatening infection of the male urethra and peri-urethral tissues
• Pathogenesis
  • Frequently a sequela of gonorrhea, urethral stricture disease, or urethral catheterization.
• Diagnosis and Evaluaiton
  • Presenting signs and symptoms include scrotal swelling (94%), fever (70%), acute urinary retention (19%), spontaneously drained abscess (11%), and dysuria or urethral discharge (5-8%).
• Management
  • Consists of immediate suprapubic urinary drainage and wide debridement

Clostridium Difficile Infection (CDI)

• Epidemiology
  • Incidence is increasing with a preponderance of the NAP1 hypervirulent strain of C. difficile found in recent epidemics.
    • The NAP1 strain is more likely to cause severe and fulminant colitis, characterized by marked leukocytosis, renal failure, hemodynamic instability, and toxic megacolon.
    • It is believed the NAP1 strain arose due to the widespread use of fluoroquinolone antibiotics.
• Management
  • Options:
    1. Oral vancomycin (more effective)
    2. Oral metronidazole
  • Neither I.V. vancomycin nor I.V. metronidazole have been found to be more effective than the oral form of the medications for treatment of CDI.
  • No role for fluoroquinolones.
  • Metronidazole should be avoided in patients on warfarin
    • Metronidazole interferes with warfarin metabolism
  • Worsening diarrhea, fever, and leukocytosis despite appropriate antibiotics is an absolute indication for surgical consultation.
    • Subtotal colectomy with end ileostomy is the procedure of choice for fulminant CD colitis nonresponsive to medications and has been documented to result in improved survival.

Questions

1. What is the mechanism of action of:
   1. TMP/SMX
   2. Nitrofurantoin
   3. Ciprofloxacin
   4. Ampicillin
   5. Fosfomycin
   6. Gentamicin
2. Which antibiotics should be avoided in patients on warfarin?

Answers

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

References

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