Disease-a-Month 61 (2015) 45–59

Contents lists available at ScienceDirect

Disease-a-Month

journal homepage: www.elsevier.com/locate/disamonth

Urinary tract infections

Sampath Kumar, MD, Ankur Dave, DO, Brian Wolf, MD,
Edgar V. Lerma, MD, FACP, FASN

Introduction

Urinary tract infections (UTIs) account for nearly 7 million office visits and 1 million emergency
department visits, resulting in 100,000 hospitalizations annually.1 UTIs are more common in women
with 33% requiring antimicrobials for at least 1 episode by the age of 24. With an estimated annual
cost of community-acquired UTIs being around 1.6 billion dollars, the financial burden is significant.1
A UTI is a microbial infection in any part of the urinary tract including the kidneys, ureters,
bladder, and urethra. Certain conditions that predispose patients to UTIs are listed in Table 1.
UTIs can be categorized anatomically. If it is localized to the bladder it is called cystitis; if there is
renal involvement it is called pyelonephritis. Cystitis and pyelonephritis can both be
subcategorized into being either an uncomplicated or complicated infection. Factors that
classify complicated UTIs include:

Diabetes
Pregnancy
Symptoms for seven or more days before seeking care
Renal failure
Urinary tract obstruction
Presence of indwelling urethral catheter stent or nephrostomy tube
Recent urinary tract procedure or instrumentation
Functional or anatomic abnormalities of the urinary tract
Renal transplant
Immunosuppression
History of urinary tract infections in childhood
In addition to cystitis and pyelonephritis there are several other conditions that can affect the
urinary tract. These include:

Chronic pyelonephritis
Emphysematous pyelonephritis
Recurrent UTIs
Catheter-associated UTIs (CAUTI)
Candiduria/funguria
Prostatitis

http://dx.doi.org/10.1016/j.disamonth.2014.12.002
0011-5029/& 2015 Mosby, Inc. All rights reserved.
46 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Table 1
Conditions predisposing to UTI.

Female
Urinary tract obstruction
Renal transplantation
Pregnancy
Immunosuppression
Diabetes
HIV with high viral load
Spinal cord injury
Neurogenic bladder
Polycystic kidney disease
Urethral catheterization
Bladder prolapse
Sexual intercourse
Vesicoureteral reflux
Urological instrumentation of surgery
Symptoms for 7 or more days before seeking care
Hospital-acquired infection
Presence of an indwelling urethral catheter, stent, nephrostomy tube, or urinary diversion
Recent urinary tract instrumentation
Functional or anatomical abnormality of the urinary tract
History of urinary tract infection in childhood

Cystitis

Basis of diagnosis

 Dysuria
 Frequency of urination
 Urgency
 Suprapubic or low back pain
 No fevers
 Positive UA

Physical examination and laboratory findings

Cystitis is usually clinically asymptomatic. On occasion, affected patients may present with
suprapubic tenderness. However, the diagnosis is commonly based on historical information.
A woman who presents in the outpatient setting with dysuria and frequency of urination
without vaginal discharge has a 96% probability of having cystitis.2 Laboratory findings can help
in guiding therapeutic management while ruling out alternative diagnoses.
A very useful test in the evaluation of UTI is a urinalysis. Nitrite and leukocyte esterase are
the 2 important aspects of a urine dipstick that can help confirm the diagnosis of a UTI.
Positive nitrites suggest the presence of gram-negative bacteria such as Escherichia coli,
Klebsiella, Proteus, and Enterobacter because these organisms convert urinary nitrates to
nitrites. This test, however, will not turn positive if gram-positive species such as
Staphylococcus or Streptococcus are the causative microbes. Leukocyte esterase is an enzyme
contained in White Blood Cells (WBCs) that is released when they undergo lysis. Its detection
is a reflection of the presence of WBCs in the urine. Normally, the concentration of WBCs is
not high enough to result in a positive leukocyte esterase lab value. However, in the presence
of pyuria, the test will become positive. Leukocyte esterase might be negative during the
early phase of an infection where the threshold has not been reached for the test to be
positive.3
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 47

Urine microscopy increases the sensitivity and specificity of a urine dipstick test. Normally no
bacteria should be seen in the urinary sediment. However, due to the presence of normal
microbial flora in the vagina and the external urethral meatus, this is not an unusual finding. In
addition, bacteria multiply rapidly if left standing for a long time at room temperature. A urinalysis
that is positive for nitrites, leukocytes esterase, and bacteria is highly suggestive of a UTI. If a
significant amount of squamous epithelia cells, defined as 415–20 per high-power field are
present, then the sample is likely contaminated and a repeat sample should be obtained. Although
the urine microscopy findings may be suggestive of a UTI, the patient should generally have
symptoms prior to treatment. If patients do not have symptoms, this entity is called asymptomatic
bacteriuria, and situations that warrant treatment are discussed in a later section. If bacteriuria is
found and a UTI is suspected a urine culture should be drawn. Generally, the presence of a urinary
culture composed of greater than 100,000 colony-forming units of a single organism in a patient
with symptoms confirms the diagnosis of a UTI (Chart 1).

Treatment

Uncomplicated cystitis
Uncomplicated cystitis is an infection limited to the urinary bladder. Uncomplicated cystitis (UC)
remains one of the most common reasons for antimicrobial use in the outpatient setting with E. coli
being the most common organism detected in 75–95% of cases. The most recent guidelines for the
management of UTI from the Infectious Disease Society of America (2010) recommend Nitro-
furantoin, Trimethoprim–Sulfamethoxazole, and Fosfomycin as first-line agents for treatment.4
Ciprofloxacin and Levofloxacin, which are also highly effective options, are considered second-line
agents because overutilization of these agents can lead to the development of drug-resistant
organisms which can contribute to colonization or growth of multidrug-resistant organisms
(MDRO).5 Amoxicillin–Clavulanate and Cefdinir are considered as third-line agents due to known
adverse effects. Current recommended drugs and dosing regimens are listed in Table 2.

Pregnant Women
Asymptomac
Symptomac with abnormal
UA (No Rx) Men undergoing
Urological
Surgeries

Excepons Spinal Cord Injuries

Microscopic Urinary Analysis Renal Transplants

Squamous Cells >10 Pyuria>10 Bacteriuria>100,000 For Younger

or Hyaline Casts (urine culture) Women and Men,
Further Analysis for Bacteriuria >1000
>10-Repeat UA
UTI Significant for UTI Significant for UTI

Check Nitrites Check Leukocyte esterase

Chart 1. Lab diagnosis flow sheet.

48 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Table 2
Empiric treatment of uncomplicated cystitis.

Drug Dosing Duration

First line
Nitrofurantoin 100 mg twice daily 5 days
Trimethoprim–Sulfamethoxazolea 160/800 mg twice daily 3 daysa
Fosfomycin 3g 1 dose

Second line
Ciprofloxacina 250 mg twice daily 3 daysa
Levofloxacin 250 mg daily 3 days

Third line
Amoxicillin–Clavulanate 875-125 mg twice daily 3–7 days
Cefdinir 300 mg twice daily 3–7 days

a
First line for cystitis in men for a duration of 7 days.

In males, the possibility of prostatitis has to be considered in the differential diagnosis of UC,
because it warrants the need for an antimicrobial with good tissue penetration. Trimethoprim–
Sulfamethoxazole and Ciprofloxacin both provide good coverage for common pathogens (based
on extrapolated studies in females). Although antimicrobial doses are the same as in women, the
guidelines recommend that the duration of therapy be extended to 7 days. Therapy shorter than
7 days has been shown to be associated with an increased incidence of recurrent infections. One
must recognize that longer courses of antimicrobial therapy can predispose to Clostridium
difficile colitis.6 Nitrofurantoin and Fosfomycin are not recommended in males primarily because
of poor tissue penetration.

Complicated cystitis
Complicated cystitis (CC) is a common complication due to overuse of antibiotics. A urine
culture should be obtained prior to initiating antimicrobials. Previous urine culture results will
help guide empiric therapy. The use of empiric Nitrofurantoin and Trimethoprim–Sulfamethox-
azole is contraindicated because of the high risk of resistance.7 First-line, empiric antimicrobials
include oral Ciprofloxacin and Levofloxacin with suggested dosages listed in Table 3. A 7-day
regimen is appropriate as long as there is absence of signs or symptoms of pyelonephritis (refer
to the section below).7 Once culture results are obtained, antimicrobials can be tailored to
include B-lactams, Nitrofurantoin, or Trimethoprim–Sulfamethoxazole.

Table 3
Empiric treatment of complicated cystitis.a

Drug Dosing Duration (days)

First line
Ciprofloxacin 500 mg twice daily 7
Levofloxacin 750 mg daily 7

Narrowing of antibiotics (based on cultures)

Nitrofurantoin (macrocrystals) 100 mg twice daily 7
Trimethoprim–Sulfamethoxazole 160/800 mg twice daily 7

Cannot tolerate orals

Ceftriaxone 1 g daily IVPB 7
Piperacillin–Tazobactam 3.375 g every 6 h IVPB 7

Cannot tolerate orals and Penicillin allergy

Aztreonam 1 g every 8 h IVPB 7

a
Always send cultures.
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 49

Parenteral therapy may be warranted in patients who cannot tolerate oral therapy. Empiric therapy
can include Ceftriaxone or Piperacillin–Tazobactam if resistant gram-negative bacilli are suspected.8
With Penicillin allergy, Aztreonam can be used. For dosage and regimen information see Table 3.

Pyelonephritis

Basis of diagnosis

● Fevers Z 381C
● Rigors and chills
● Flank pain or costovertebral angle tenderness
● Positive urine cultures
● Leukocytosis
Patients with pyelonephritis will present with similar symptoms and laboratory findings seen in
cystitis, but will also have signs of systemic inflammation and flank pain. In such patients, a Gram
stain can be useful in guiding immediate empiric antimicrobial selection. It is important to quickly
and aggressively treat these patients to prevent severe complications that can arise from the
underlying infection.

Treatment

Uncomplicated pyelonephritis
With uncomplicated pyelonephritis (UP) it is imperative to obtain urine culture studies prior
to initiating empiric antimicrobial therapy. Currently, the preferred empiric agent for use in UP is
oral Ciprofloxacin. In populations where resistance patterns to Ciprofloxacin are less than 10%,
treatment with Ciprofloxacin alone will suffice9. In regions where resistance patterns are above
10%, a one-time dose of IV Ceftriaxone or a 24-h dose of an aminoglycoside (e.g., gentamicin)
should be initiated followed by Ciprofloxacin as outlined in Table 4.
In patients in whom Ciprofloxacin is contraindicated, including those who cannot tolerate
oral medications, the second line treatment should include IV Ceftriaxone or Aminoglycosides
followed by oral Trimethoprim–Sulfamethoxazole as listed in Table 4. Treatment without an
initial dose of a parenteral agent has been shown to cause higher treatment failure rates.9

Table 4
Empiric treatment of uncomplicated pyelonephritis.

Condition Drug Dosing Duration

(days)

First line Ciprofloxacin 500 mg twice daily 7–14

Ceftriaxone followed by 1 g once of Ceftriaxone followed by 7–14
Ciprofloxacin Ciprofloxacin 500 mg twice daily
Aminoglycoside followed by 1.5 mg/kg/dose q 8 h for 24 h followed by 7–14
Ciprofloxacin Ciprofloxacin 500 mg twice daily

Second line/cannot Ceftriaxone followed by 1 g once of ceftriaxone followed by 14

tolerate orals Trimethoprim– Trimethoprim–Sulfamethoxazole 160/800 mg
Sulfamethoxazole twice daily7
Aminoglycoside followed by 1.5 mg/kg/dose q 8 h for 24 h followed by 14
Trimethoprim– Trimethoprim–Sulfamethoxazole 160/
Sulfamethoxazole 800 mg7

Cannot tolerate orals Aztreonam 1 g every 8 h IVPB 7

and Penicillin
allergy
50 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Although oral B-lactams are not recommended for initial empiric use, if the culture results show
B-lactam sensitivity, it is reasonable to utilize them.

Complicated pyelonephritis
All patients with suspected complicated pyelonephritis (CP) should be treated aggressively in
an inpatient setting. As in UP, urine cultures should initially be sent for analysis before starting
empiric therapy. Initial empiric antimicrobial selection should be based on prior culture results.
Antimicrobials alone may not suffice in the presence of anatomical abnormalities involving the
urinary tract. In patients who are critically ill, it is important to look for possible perinephric
abscesses or intrarenal obstruction as these patients may need prompt drainage to treat their
infection. Diagnostic imaging can include a CT or renal ultrasound to further delineate urinary
tract abnormalities. Empiric antimicrobials include Ceftazidime, Cefepime, Piperacillin–
Tazobactam, Aztreonam, Meropenem, or Imipenem based on local gram-negative-resistance
patterns (Table 5).10 Duration of therapy should last for 14 days. Once susceptibility patterns are
known from the initial urine culture, antimicrobials can be adjusted accordingly. The presence of
gram-positive cocci on initial Gram stain generally suggests the presence of enterococci, which
should be treated with oral Amoxicillin or IV Ampicillin. For Vancomycin-resistant enterococci
(VRE), Daptomycin should be considered (Table 5). For all cases of Methicillin-Resistant
Staphylococcus aureus (MRSA) UTI it is important to rule out alternative sources of infection.
Expeditious testing for bacteremia, skin and soft tissue infections, line infections, and device
infections should be pursued. For diagnosis of endocarditis an echocardiogram is necessary.10
Table 5 lists the recommended antimicrobial choices for CP.

Emphysematous pyelonephritis

Basis of diagnosis

 Presence of gas within the kidney parenchyma

 Sepsis
 Leukocytosis
 Cultures positive for gas-forming bacteria

Emphysematous pyelonephritis (EPN) is a life-threatening complication of poorly controlled

diabetes, characterized by bacterial production of gas within the kidney parenchyma. Up to 90%
of patients who develop EPN have poorly controlled diabetes mellitus. Early diagnosis and
treatment may help avoid emergency nephrectomy. There is a 21% mortality rate from EPN,

Table 5
Empiric treatment of complicated pyelonephritis.

Condition Drug Dosing Duration

Gram negative Ceftazidime 3–6 g daily 14 days

Cefepime 2–4 g daily 14 days
Piperacillin–Tazobactam 18 g daily 14 dose
Aztreonam 3–8 g daily 14 days
Meropenem 1.5–3 g daily 14 days
Imipenem 2 g daily 14 days

Gram positive
Enterococci bacteremia Amoxicillin 500 mg every 8 h 14 days
Ampicillin 2 g every 6 h IVPB 14 days
VRE bacteremia Daptomycin 6 mg/kg every 24 h IVPB 14 days
MRSA bacteremiaa Vancomycin Pharmacy dosing 14 days

a
Workup for endocarditis.
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 51

which is primarily attributable to severe sepsis. The incidence of EPN is much higher in females
due to their increased susceptibility to urinary tract infections. Factors involved in the
pathogenesis of this condition include the triad of (1) high glucose levels, (2) the presence of
gas-forming bacteria, and (3) impaired tissue perfusion leading to anaerobic metabolism. Gram-
negative facultative anaerobic bacteria ferment glucose and lactate, resulting in the formation
and accumulation of carbon dioxide and hydrogen at the site of inflammation.11
Gram-negative bacteria, including E. coli and Klebsiella pneumonia, remain the most common
infecting organisms. Empiric antimicrobials should be selected to target these organisms. In the
late 1980s, the accepted treatment of EPN was emergent nephrectomy or open surgical drainage,
resulting in a reported mortality rate of 40–50%. Significant advances in Percutaneous Catheter
Nephrostomy (PCN) tube placement now serve as an alternative treatment option. PCN should
be performed on patients with localized areas of gas with preserved functioning renal tissue. The
drainage tubes should remain in place until follow-up CT scans show resolution of EPN.
Antimicrobial agents used for the treatment of EPN are similar to those used for complicated
pyelonephritis (Table 5). However, the duration of treatment should be extended to a minimum
of 4 weeks with serial CT scans prior to discontinuing antimicrobials.

Pyonephrosis

Urinary tract obstruction in the presence of pyelonephritis may result in pyonephrosis.

Pyonephrosis is the presence of pus within the urological system. Patients with pyonephrosis
can decompensate rapidly due to obstruction. Thus, early recognition and treatment is of
paramount importance.
Similar to an abscess, pyonephrosis is typically associated with fever and chills. It may be caused by
a broad spectrum of pathologic conditions involving either an ascending infection of the urinary tract
or by hematogenous spread of a bacterial pathogen. Risk factors for pyonephrosis include
immunosuppression due to medications (e.g., steroids), diseases [e.g., diabetes mellitus or acquired
immunodeficiency syndrome (AIDS)], or any anatomical urinary tract obstruction [e.g., stones, tumors,
ureteropelvic junction (UPJ) obstruction, pelvic kidney, or horseshoe kidney]. Treatment doses and
regimens are similar to those of CP (Table 5), but the duration of therapy is extended to 4–6 weeks.

Chronic pyelonephritis

Basis of diagnosis

 Symptoms of acute pyelonephritis except with low-grade fevers

 Costovertebral angle tenderness which is less severe as compared to acute pyelonephritis
 Recurrent and inadequately treated pyelonephritis
 Ultrasound or CT scan shows renal scarring
 Underlying urinary tract obstruction

Chronic pyelonephritis is characterized by renal inflammation and fibrosis induced by

recurrent or persistent renal infection, vesicoureteral reflux, or other causes of urinary tract
obstruction such as nephrolithiasis. The diagnosis of chronic pyelonephritis is based on imaging
studies such as ultrasound or CT scan. It occurs almost exclusively in patients with major
anatomical abnormalities, most commonly in young children with vesicoureteral reflux (VUR).
VUR is a congenital condition that results from incompetence of the ureterovesical valve due
to a short intramural segment. VUR is present in 30–40% of young children with symptomatic
UTIs and in almost all children with renal scars. It may also be acquired in patients with a flaccid
bladder due to spinal cord injury. The differential diagnosis includes analgesic nephropathy,
renal tuberculosis, renal dysplasia, xanthogranulomatous pyelonephritis, and renal malakopla-
kia. Treatment doses and regimens are similar to CP (Table 5); however, the duration of therapy
is extended to 4–6 weeks. If residual kidney function is reduced, surgical intervention in addition
to intravenous antibiotics may be warranted.
52 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Asymptomatic bacteriuria

Asymptomatic bacteriuria (AB) is defined as 2 consecutive clean-catch midstream bacterial

cultures with colony counts 4 105 CFU/mL in females consisting of the same organism. It is also
defined as a single clean-catch specimen in men or a single catheterized specimen in all patients.
Treatment is only warranted in all pregnant women, men undergoing urological procedures that
include mucosal bleeding, and all renal transplant patients. Treatment includes the same doses
and regimens as seen in uncomplicated cystitis (Table 2). It is unnecessary to treat patients who
are diabetic, not pregnant, those with spinal cord injuries, or catheterized patients if no systemic
symptoms are present.12

Catheter-associated urinary tract infections

Basis of diagnosis

 Presence of indwelling Foley catheter

 Costovertebral angle tenderness
 Rigors and chills
 Delirium
 Encephalopathy
 Polymicrobial etiology

Catheter-associated UTI (CAUTI) is the most common healthcare-associated infection in the

world. Most cases of CAUTI are usually preventable by avoiding inappropriate use of Foley
catheters. The most effective means to decrease the incidence of CAUTI is to reduce the use of
Foley catheters or to discontinue them as soon as possible. CAUTI is seen in patients with
indwelling Foley catheters or in those in whom a Foley catheter was discontinued within the last
48 hours using a clean-catch urine sample. The diagnosis can be made when bacterial counts are
greater than 1000 CFU/mL and show more than one bacterial species. In a study, CAUTI patients
lacked signs of fever, urgency, pain, or dysuria typically seen in cystitis. Instead, patients
displayed CVA tenderness, rigors, and new-onset delirium.13 It is important to note that foul-
smelling urine does not warrant the diagnosis of CAUTI.14 In the absence of pyuria, an alternative
diagnosis should be pursued. In patients with spinal cord injury, spasticity, autonomic
dysreflexia, or a sense of unease may be the presenting symptoms of a CAUTI.
In suspected patients with CAUTI, the Foley catheter should first be replaced followed by a
urinalysis with cultures prior to initiating antimicrobials.15 Duration of therapy depends on the
clinical response. In those who respond rapidly to treatment, 7 days of therapy is sufficient. In
those with delayed response, 10–14 days of therapy should be continued regardless of the status
of the Foley catheter.16

Recurrent UTIs and chemoprophylaxis

Women with more than 3 recurrent UTIs yearly should be considered for more aggressive
prophylactic regimens in addition to behavioral modification. Women whose recurrent UTIs are
associated with sexual intercourse should be offered postcoital prophylaxis. Affective regimens
include a single dose of postcoital Nitrofurantoin 100 mg, Trimethoprim–Sulfamethoxazole
80/400 mg mg, or Cephalexin 500 mg. Alternative regimens include Trimethoprim–Sulfame-
thoxazole 40/200 mg every night or 3 times weekly or Nitrofurantoin 50–100 mg every night or
3 times weekly. These regimens have been shown to be safe and effective even after 5 years of
use. However, after 6–12 months, antimicrobial holiday is warranted because as many as 30% of
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 53

women experience a prolonged UTI-free period. Prophylaxis may be reinstituted if the patient
again develops recurrent UTIs.

Funguria

Funguria is a common phenomenon encountered in hospitalized patients especially those in

an ICU/long-term care setting. Funguria is generally a benign condition. Among healthy adults,
yeast are encountered in o 1% of urine specimens but account for 5–10% of positive urine
culture results in hospital and tertiary care patients. The majority of cases occur in patients with
indwelling bladder catheters.17 The majority of these infections are due to Candida species. There
are multiple predisposing factors for candiduria and Candida UTIs (Table 6).
When candidal organisms are discovered in the urine, one must determine whether this is due
to an infection of the upper or lower urinary tracts, colonization of the bladder, or contamination of
the urine sample. Contamination can be easily differentiated from colonization or infection by
obtaining a repeat culture. It is important to note that most patients with candiduria do not have a
significant infection. Individuals who have a true infection will present with signs and symptoms as
seen in cystitis, which can progress to those seen in pyelonephritis. For critically ill patients,
candiduria should initially be regarded as a potential marker for the presence of invasive
candidiasis, and workup should be initiated to rule out disseminated Candida infection. Similar to
cystitis, pyuria in the presence of yeast is a useful tool in the diagnosis of Candida UTI, unless the
patient has an indwelling catheter.18
Treatment of candiduria is based on symptoms since the majority of cases indicating
candiduria represent colonization, contamination, or non-invasive candidiasis. Even if an
infection of the urinary tract is confirmed by Candida species, antifungal therapy is not always
warranted. It is helpful to divide patients with candiduria into 5 groups: (1) asymptomatic
candiduria (previously healthy), (2) asymptomatic candiduria with predisposing factors
discussed above (outpatient), (3) asymptomatic candiduria with predisposing factors discussed
above (inpatient), (4) symptomatic candiduria (cystitis, pyelonephritis, prostatitis, epididymo-
orchitis, or urinary tract fungus balls), and (5) clinically unstable patient with candiduria. A list of
treatment agents are listed in Table 7.19

Prostatitis

Prostatitis is an inflammatory condition that affects the prostate. Nearly 15% of all men will
experience prostatitis like symptoms during their lifetime.20 Although some cases of prostatitis
are clearly infectious, most men who are diagnosed with this will have no evidence of bacterial
infections. Currently, prostatitis remains more prevalent in men less than 50 years old. Other risk
factors include functional or anatomical abnormalities, urogenital instrumentation, chronic
indwelling bladder catheterization, intermittent bladder catheterization, and prostate biopsy.21
However, many men who develop acute prostatitis have no clear risk factors.

Table 6
Predisposing factors for candiduria.

Diabetes mellitus Broad-spectrum antibiotics

Renal transplantation Bladder dysfunction
Extreme of ages Urinary stasis
ICU admission Nephrolithiasis
Prolonged hospitalization Instrumentation of the urinary tract
Indwelling urinary tract devices Structural or congenital abnormalities of the urinary tract
54 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Table 7
Treatment of candiduria.

Condition Drug/treatment Dosing Duration

Candida cystitis and pyelonephritis Fluconazole 400–800 mg IV daily 2–4 weeks

Flucytosine 25 mg/kg PO 4 times a day 2–4 weeks
Amphotericin Ba 0.3–1 mg/kg IV 1 or more doses

Candida prostatitis and epididymo-orchitis Fluconazole 400 mg daily 4 weeks

Surgical drainage

Fungus ball Amphotericinb CBIb 1–4 weeks

Fluconazole 400 mg daily 4 weeks
Flucytosine 25 mg/kg PO 4 times a day 2–4 weeks
Surgical drainage

a
Followed by orals such as Fluconazole.
b
Continuous bladder irrigation.

Currently, the NIH classifies prostatitis into 4 categories.22 These include acute and chronic
bacterial prostatitis, chronic pelvic pain syndrome (CPPS) formerly known as chronic
nonbacterial prostatitis, and asymptomatic inflammatory prostatitis. CPPS is categorized into
2 subcategories including inflammatory and non-inflammatory CPPS based on the presence or
absence of prostatic inflammation. This classification system is useful for physicians because it
will help determine therapeutic options along with their duration of therapy.

Acute bacterial prostatitis

Basis of diagnosis

 Rigors/fevers 4381C
 Tender prostate
 Perineal/rectal pain
 Positive cultures

Acute bacterial prostatitis (ABP) is an acute infection involving the prostate. It is categorized
as class 1 according to the NIH classification (Table 8). Patients who are young or with chronic
indwelling Foley catheters are more at risk of developing ABP; however, ABP can present in all
adult males. Patients with ABP will present as being acutely ill. Signs and symptoms include
acute onset of fever, chills, dysuria, urgency, and pelvic pain. Patients may complain of dribbling
when urinating which can lead to urinary retention. When a patient presents with these
symptoms, a digital rectal exam should be performed. Vigorous prostatic massage should be
avoided due to an increase risk of causing bacteremia.23 A tense boggy and exquisitely tender
prostate on examination supports a diagnosis of ABP. Laboratory findings commonly found in
ABP include systemic leukocytosis, pyuria, bacteriuria, and elevations of serum prostate-specific
antigen (PSA) levels.
When a patient presents with these signs and symptoms along with supporting laboratory
findings, a urine Gram stain and culture should be sent prior to starting empiric antimicrobials. The
type of microorganisms causing acute prostatitis has been shown to contain increased virulence
properties allowing them to infect the prostate.24 The most common causative organisms are
gram-negative urinary pathogens. These include E. coli, followed by Klebsiella, Proteus,
Pseudomonas, and Enterococcus.25 In catheter-associated cases the most causative organisms
include enteric gram-negative rods and hospital-acquired enterococci. Patients at risk of sexually
transmitted infections (STIs) can be infected with both Neisseria gonorrhea and Chlamydia
trachomatis bacteria. Acute staphylococcal prostatitis, while being very rare, has also been shown to
cause acute prostatitis usually through hematologic spread or rarely in patients with chronic
indwelling Foley catheters.26
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 55

Table 8
NIH classification of prostatitis.

NIH Pain Urine Pyuria NIDDK Description Essentials of diagnosis

category culture (current)

I Yes Yes Yes Acute Acute bacterial infection of the prostate. Fever4381C, tender
prostatitis Patients will be acutely ill and will prostate, perineal
require urgent antimicrobial therapy pain, and positive
cultures
II 7 Yes Yes Chronic History of recurrent UTI symptoms or Positive cultures and
bacterial documented infection with same pyuria
prostatitis organism. Will require antimicrobial
treatment but will appear less ill
compared to acute prostatitis
IIIa Yes No Yes Inflammatory Presentation with dysuria, urgency, and Post-prostatic massage
CPPS/CP frequency. Both type a and type b will showing elevated
have culture negative results pyuria and negative
cultures
IIIb Yes No No Non- No increase in pyuria
inflamma- post prostatic
tory CPPS/CP massage and
negative cultures
IV No No Yes Asymptomatic Pyuria in the presence of an Asymptomatic pyuria
inflamma- asymptomatic patient
tory
prostatitis

NIH—National Institute of Health; NIDDK—The National Institute of Diabetes and Digestive and Kidney Diseases;
CP—chronic prostatitis; CPPS—chronic pelvic pains syndrome.

The preferred antibiotic regimen for ABP should initially consist of IV fluoroquinolones.
Alternative antibiotics include Trimethoprim–Sulfamethoxazole. In patients with ABP who have
chronic indwelling Foley catheters, IV fluoroquinolones or Imipenem are good empiric choices. If an
STI is suspected ceftriaxone and azithromycin should be considered. Patients typically respond
quickly after the initiation of antibiotics. In cases where patients do not respond quickly, prostatic
abscesses should be considered. These can be diagnosed with either a prostatic ultrasound or a CT
of the pelvis with contrast. Other complications of ABP include bacteremia, epididymitis, chronic
bacterial prostatitis, and metastatic infection including spinal or sacroiliac infection.21 Table 9 lists
the dosing and duration of therapy for acute bacterial prostatitis.

Chronic prostatitis

Basis of diagnosis

 Frequency
 Dysuria
 Urgency
 Perineal discomfort/pelvic pain
 Positive cultures
 Pyuria

Chronic bacterial prostatitis (CBP) is the second class of prostatitis categorized by the NIH.22 It
encompasses a syndrome of documented infection of the prostate with recurrent urologic
symptoms. This differs from chronic pelvic pain syndrome where there is no evidence of
bacterial infections. Patients with ABP have an 8% chance of progressing to CBP. Several risk
factors increase the chance of developing CBP. These include prior urinary tract manipulation
56 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Table 9
Treatment of acute bacterial prostatitis.a

Treatment Dosing Duration (weeks)

Ciprofloxacinb,c 500 mg orally twice daily 6

Levofloxacinb,c 500 mg orally once daily 6
Trimethoprim–Sulfamethoxazole 160/800 mg orally twice daily 6

a
May de-escalate based on sensitivities but should treat for a 6-week duration.
b
May substitute with intravenous medication if patient cannot tolerate oral medications.
c
First line.

including Foley catheters or urogenital surgery, diabetes, and BPH.27 It is important after a
patient has ABP to try to reduce these risk factors as much as possible to decrease the risk of
progression to CBP.
The presentation of CBP in patients covers a wide spectrum. Classically chronic bacterial
prostatitis will present with symptoms lasting greater than 3 months. The most common
symptoms are those of relapsing urinary tract infections (frequency, dysuria, urgency, and
perineal discomfort), with the same infectious organism being cultured during each event.
However, relapsing urinary symptoms are only seen in less than 50% of patients.26 Other
presenting symptoms include pain in the perineum, lower abdomen, testicles, penis, or with
ejaculation. Some patients may only present with asymptomatic bacteriuria seen on recurrent
urinary cultures. On physical exam, the prostate may be enlarged, tender, or nodular; however,
frequently the prostate exam is normal.
Laboratory evaluation should include a urinalysis with urinary cultures. Signs of inflammation in
a urinalysis should be followed by a 2-glass test. Previously, the diagnostic standard for CBP was the
Meares–Stamey 4-glass test, but it is no longer used by urologists because it is a cumbersome and
difficult test. A variation of the 4-glass test is known as the Nickel premassage and postmassage
test, or the 2-glass test. In this test, the patient is first asked to collect a midstream urine sample
into a clean-catch cup. The patient is then asked to stop urinating. The physician then massages the
prostate from the periphery toward the midline several times. Following the massage, the patient is
asked to provide more urine for a postmassage urine analysis and culture. This test is composed of
2 samples of urine collected both pre- and post-prostatic massage to detect the presence of
inflammation expressed from the prostate. A positive test is defined by increased postmassage
pyuria at least 10 times greater than pre-prostatic massage or a post-prostatic massage leukocyte
count greater than 1000 per microliter.28 It should be noted that the degree of increased pyuria
does not correlate with the severity of symptoms.26 To diagnose CBP, in addition to pyuria, there
must be positive urine cultures. If the urine cultures are negative, then a diagnosis of inflammatory
chronic pelvic pain syndrome is made.
Unlike in acute bacterial prostatitis, treatment for CBP can usually be delayed until culture
and susceptibility results are available because of the chronicity of the infection. Urogenital
organisms similar to ABP remain the most common causes of CBP. The preferred antimicrobials,
similar to ABP, remain fluoroquinolones because of their high concentrations in the prostate.
Alternative antimicrobials should be used in cases of documented or suspected fluoroquinolone
resistance or the presence of staphylococcal infection (Table 10). Antimicrobial therapy should
be continued for 4–6 weeks. If patients after treatment have resolution of their symptoms, there
is no need to treat asymptomatic bacteriuria if present. If symptoms persist, a repeat urine
culture should be drawn to be sure the organism is still susceptible to the antimicrobial being
used. Antimicrobials at that time should be extended for a prolonged course and possibly at a
higher dose if the organism remains susceptible. If the organism is resistant, an alternative agent
should be used. If a patient has resolution of their symptoms after treatment but relapses later,
the patient can be referred to a urologist to see if they have any prostatic stones. If present, these
can be surgically removed. If there are none present, the patient may need prophylactic
antimicrobial suppression therapy to prevent relapses.26
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 57

Table 10
Treatment of chronic bacterial prostatitis.

Organism Treatment Dosage Duration

(weeks)

Enterobacteriaceae (Enterococcus Ciprofloxacin 500 mg oral every 4–6

species) 12 h
Levofloxacin 500 mg oral every 4–6
24 h
Trimethoprim– 1 DS tablet twice daily 4–6
Sulfamethoxazole

Staphylococcus species Azithromycin 500 mg oral daily 4–6

Doxycycline 100 mg oral twice 4–6
daily

DS—double strength.

Chronic pelvic pain syndrome (formerly nonbacterial prostatitis) and chronic prostatitis

Chronic Pelvic Pain Syndrome is a disease where patients will present with chronic urinary
tract symptoms. These symptoms include increased urinary frequency, dysuria, and urgency. The
main difference between CBP and CPPS is that bacterial cultures will be negative in CPPS as
compared to CBP. Additionally, the vast majority of patients with CPPS will have a negative
physical exam. The NIH subcategorizes CPPS into 2 groups. These are based on the presence or
absence of inflammation. The presence of inflammation in the two-glass test, as described
above, represents Class 3a inflammatory CPPS. The absence of elevated pyuria after prostatic
massage represents Class 3b non-inflammatory CPPS. Both subgroups of Class 3 CPPS may have
pyuria on a urinalysis, but it is the presence or absence of elevated pyuria in relation to a pre and
post prostatic massage that differentiates the 2 forms of CPPS.
Treatment options for both inflammatory and non-inflammatory CPPS are the same.
Currently, antimicrobial therapy for the treatment of CPPS remains controversial. It is believed
that antimicrobials may be beneficial due to their anti-inflammatory properties, but there have
been studies showing no additional benefit when compared to placebo.26 It is appropriate to
treat with antimicrobials in patients who have never received antibiotics for CPPS treatment in
the past. Current recommended antimicrobials are the same as those used in CBP (Table 10). If
they have received antimicrobial treatment in the past, studies have shown that there is no
additional benefit for repeated therapy.29 An alternative treatment option includes the use of
alpha-blockers for 12–14 weeks in alpha-blocker-naïve patients. There appears to be no role for
5-alpha reductase inhibitors or surgery in the treatment of CPPS. Other treatment options
include biofeedback, but there is currently limited data on this treatment modality.

Asymptomatic inflammatory prostatitis

Asymptomatic inflammatory prostatitis (AIP) is the fourth class of the NIH classification of
prostatitis. Patients with AIP will be asymptomatic in their presentation but will have
unexplained pyuria on routine urinalysis. Their physical exam will be benign along with negative
urine culture results. Currently there is no treatment necessary for AIP. However, it is important
to document AIP in the patient's chart to prevent unnecessary urinary testing in the future.

Conclusion

Urinary tract infections constitute a multitude of disease processes seen in patients. The first
and most important question is if the patient is symptomatic. This ranges from having increased
frequency and dysuria in cystitis to acutely septic patients in pyelonephritis and acute prostatitis.
58 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59

Workup should include a urinalysis looking for evidence of pyuria followed by urine cultures
and Gram stains. If acute bacterial prostatitis is suspected, gentle palpation should be done to
verify one's suspicion. Depending on the suspected diagnosis, empiric antimicrobials may be
started depending on patients' risk factors and presentation. Once antimicrobial susceptibilities
return, it is generally advisable to de-escalate therapy. The presence of funguria in a urine
culture is generally a benign finding and does not require treatment. Treatment is only required
if the patient is symptomatic with pyuria. If the patient is unstable, it is recommended to look for
disseminated infection and treat the patient aggressively.
If chronic prostatitis is suspected, a pre- and post-prostatic massage urine specimen should
be sent to determine the presence or absence of prostatic inflammation and infection. This will
help determine if antimicrobials should be considered or if alternative therapies should be
sought. As a whole, urinary tract infections remain one of the most common infections
encountered by primary care physicians, and we hope this article helps to provide a solid
foundation in the diagnosis and treatment of these diseases.

Acknowledgements

The authors would like to acknowledge Dr. Amar Chadaga and Dr. Armand Krikorian for their
insightful review of this manuscript.

References

1. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon. 2003;49(2):
53–70. http://dx.doi.org/10.1067/mda.2003.7.
2. Fauci AS, Braunwald E, Kasper DL, et al., editors. Harrison’s Principles of Internal Medicine. 17th ed. New York: The
Mcgraw-Hill Companies; 2008:1820–1827.
3. Lerma EV, Slivka K. Urinalysis. Medscape 2013:1–5. 〈http://emedicine.medscape.com/article/2074001-overview〉;
Accessed 12.08.14.
4. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute
uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America
and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–e120. http://dx.
doi.org/10.1093/cid/ciq257.
5. Paterson DL. “Collateral damage” from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004;38(suppl
4):S341–S345. http://dx.doi.org/10.1086/382690.
6. Drekonja DM, Rector TS, Cutting A, Johnson JR. Urinary tract infection in male veterans: treatment patterns and
outcomes. JAMA Intern Med. 2013;173(1):62–68. http://dx.doi.org/10.1001/2013.jamainternmed.829.
7. Wang A, Nizran P, Malone MA, Riley T. Urinary tract infections. Prim Care. 2013;40(3):687–706. http://dx.doi.org/
10.1016/j.pop.2013.06.005.
8. Hooton TM, Calderwood SB, Bloom A. Acute Complicated cystitis and pyelonephritis. 〈www.uptodate.com〉; Accessed
06.04.14.
9. Talan DA, Stamm WE, Hooton TM, et al. Comparison of Ciprofloxacin (7 days) and Trimethoprim–Sulfamethoxazole
(14 days) for acute uncomplicated pyelonephritis in women. J Am Med Assoc. 2000;283(12):1583.
http://dx.doi.org/10.1001/jama.283.12.1583.
10. Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th
ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2010; p 957–985.
11. Katie Pojak, Asif Raza, Rafique Akkib, Gurinder Sandhu SM. Emphysematous PYelonephritis: a rare but potentially
life-threatening complication of poorly controlled diabetes. Br J Diabetes Vasc Dis. 2013;13(3):155–157.
12. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America guidelines for
the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40(5):643–654. http://dx.doi.
org/10.1086/427507.
13. Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely symptomatic. 2014:2-6.
14. Walker S, McGeer A, Simor AE, Armstrong-Evans M, Loeb M. Why are antibiotics prescribed for asymptomatic
bacteriuria in institutionalized elderly people? A qualitative study of physicians' and nurses' perceptions.
CMAJ. 2000;163(3):273–277. (Accessed 04.06.14). http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=
80288&tool=pmcentrez&rendertype=abstract.
15. Grahn D. Validity of urinary catheter specimen for diagnosis of urinary tract infection in the elderly. Arch Intern Med.
1985;145(10):1858. http://dx.doi.org/10.1001/archinte.1985.00360100120020.
16. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract
infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.
Clin Infect Dis. 2010;50(5):625-663. http://dx.doi.org/10.1086/650482.
17. Sobel JD, Fisher JF, Kauffman CA, Newman CA. Candida urinary tract infections—epidemiology. Clin Infect Dis. 2011;52
(suppl 6):S433–S436. http://dx.doi.org/10.1093/cid/cir109.
 S. Kumar et al. / Disease-a-Month 61 (2015) 45–59 59

18. Fisher JF, Kavanagh K, Sobel JD, Kauffman CA, Newman CA. Candida urinary tract infection: pathogenesis. Clin Infect
Dis. 2011;52(suppl 6):S437–S451. http://dx.doi.org/10.1093/cid/cir110.
19. Fisher JF, Sobel JD, Kauffman CA, Newman CA. Candida urinary tract infections—treatment. Clin Infect Dis. 2011;52
(suppl 6):S457–S466. http://dx.doi.org/10.1093/cid/cir112.
20. Roberts RO, Lieber MM, Rhodes T, Girman CJ, Bostwick DG, Jacobsen SJ. Prevalence of a physician-assigned diagnosis
of prostatitis: the Olmsted County study of urinary symptoms and health status among men. Urology. 1998;51
(4):578–584. http://www.ncbi.nlm.nih.gov/pubmed/9586610.
21. Acute bacterial prostatitis. 〈http://www.uptodate.com/contents/acute-bacterial-prostatitis?source=search_result&
search=prostatitis&selectedTitle=1  95〉; Accessed 11.08.14.
22. Krieger J. NIH consensus classification and definition of prostatitis. J Am Med Assoc. 1999;281:236–237.
23. Millán-Rodríguez F, Palou J, Bujons-Tur A, et al. Acute bacterial prostatitis: two different sub-categories according to
a previous manipulation of the lower urinary tract. World J Urol. 2006;24(1):45–50. http://dx.doi.org/10.1007/
s00345-005-0040-4.
24. Krieger JN, Dobrindt U, Riley DE, Oswald E. Acute Escherichia coli prostatitis in previously health young men:
bacterial virulence factors, antimicrobial resistance, and clinical outcomes. Urology. 2011;77(6):1420–1425. http:
//dx.doi.org/10.1016/j.urology.2010.12.059.
25. Etienne M, Chavanet P, Sibert L, et al. Acute bacterial prostatitis: heterogeneity in diagnostic criteria and
management. Retrospective multicentric analysis of 371 patients diagnosed with acute prostatitis. BMC Infect Dis.
2008;8:12. http://dx.doi.org/10.1186/1471-2334-8-12.
26. Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clin Infect Dis. 2010;50(12):1641–1652. http://dx.doi.
org/10.1086/652861.
27. Yoon B Il, Kim S, Han D-S, et al. Acute bacterial prostatitis: how to prevent and manage chronic infection? J Infect
Chemother. 2012;18(4):444–450. http://dx.doi.org/10.1007/s10156-011-0350-y.
28. Nickel JC, Shoskes D, Wang Y, et al. How does the pre-massage and post-massage 2-glass test compare to the
Meares–Stamey 4-glass test in men with chronic prostatitis/chronic pelvic pain syndrome? J Urol. 2006;176(1):119–
124. http://dx.doi.org/10.1016/S0022-5347(06)00498-8.
29. Murphy AB, Macejko A, Taylor A, Nadler RB. Chronic prostatitis: management strategies. Drugs. 2009;69(1):71–84.
http://dx.doi.org/10.2165/00003495-200969010-00005.