Epidemiology
Demographics
- Outpatient UTI Accounts for 7 Million Office Visits Per Year in US
Sex and Age-Related Factors Associated with Urinary Tract Infection
- Female UTI
- Incidence of UTI Increases Markedly After Onset of Sexual Actvity in Adolescence
- Incidence of Symptomatic UTI in Sexually Active Females (In a University Population): 0.5-0.7 cases per person-year
- Risk Factors
- Sexual Intercourse
- Recent Spermicide Use
- History of UTI
- Risk Factors
- Incidence of Cystitis in Post-Menopausal Female: 0.07 cases per person-year
- Incidence of Pyelonephritis: 12-13 cases per 10k females per year (lower incidence than that for cystitis)
- Male UTI
- Incidence: 5-8 UTI per 10k young adult males per year
- Most Male UTI’s Occur in Infants and Elderly (Usually Associated with Urologic Abnormalities or Instrumentation)
- However, UTI May Occur in Males age 15-50 y/o (with Risk Factors Being Anal Insertive Intercourse and Lack of Circumcision)
- Factors Related to Lower Incidence of Symptomatic Bacteruria/Symptomatic UTI in Males than Females
- Longer Urethral Length
- Drier Peri-Urethral Environment: with less frequent peri-urethral colonization
- Antibacterial Substances Contained in Prostatic Fluid
Factors Suggesting “Complicated” Urinary Tract Infection
- Demographic Features
- Advanced Age
- Male Sex
- Pregnancy (see Pregnancy)
- Comorbid Conditions
- Diabetes Mellitus (see Diabetes Mellitus)
- History of a Childhood Urinary Tract Infection
- Immunosuppression
- Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
- Renal Transplantation (see Renal Transplant)
- Infection-Related Characteristics
- Hospital-Acquired Urinary Tract Infection
- Recent Antibiotic Use
- Recent Urinary Tract Instrumentation
- Resistant Urinary Pathogen
- Symptoms For At Least 7 Days Before Seeking Medical Attention
- Urinary Tract Functional/Anatomic Abnormalities
- Benign Prostatic Hypertrophy (BPH) (see Benign Prostatic Hypertrophy)
- Urethral Stricture (see Urethral Stricture)
- Urinary Tract Instrumentation
- Foley Catheter (see Foley Catheter)
- Nephrostomy
- Urinary Diversion
- Urinary Tract Stent
- Urinary Tract Obstruction
Etiology
- Candida Albicans (see Candida)
- Clinical Manifestations
- Emphysematous Cystitis
- Clinical Manifestations
- Chlamydia Trachomatis (see Chlamydia Trachomatis): may present with combination of acute urinary symptoms, pyuria, and a negative urine culture in young sexually active female
- Citrobacter (see Citrobacter)
- Clostridium Perfringens (see Clostridium Perfringens)
- Clinical Manifestations
- Emphysematous Cystitis
- Clinical Manifestations
- Enterobacter (see Enterobacter)
- Clinical Manifestations
- Emphysematous Cystitis: may occur with Enterobacter Aerogenes (see Enterobacter Aerogenes)
- Clinical Manifestations
- Escherichia Coli (see Escherichia Coli)
- Epidemiology
- Most common etiology of UTI: accounts for 75-95% of both male and female UTI cases
- Clinical Manifestations
- Emphysematous Cystitis: most common microbial etiology of emphysematous cystitis
- Emphysematous Pyelonephritis
- Epidemiology
- Herpes Simplex Virus (HSV1 or HSV2) (see Herpes Simplex Virus): may present with combination of acute urinary symptoms, pyuria, and a negative urine culture in young sexually active female
- Klebsiella (see Klebsiella)
- Epidemiology: common etiology
- Clinical Manifestations
- Emphysematous Cystitis: may occur with Klebsiella Pneumoniae (see Klebsiella Pneumoniae)
- Emphysematous Pyelonephritis: may occur with Klebsiella Pneumoniae (see Klebsiella Pneumoniae)
- Neisseria Gonorrhoeae (Gonococci) (see Neisseria Gonorrhoeae): may present with combination of acute urinary symptoms, pyuria, and a negative urine culture in young sexually active female
- Mycoplasma Genitalium (see Mycoplasma Genitalium): may present with urethritis or cystitis
- Mycoplasma Hominis (see Mycoplasma Hominis): may present with pyelonephritis
- Other Fungi: usually involve the kidney as a result of disseminated infection
- Aspergillus (see Aspergillus)
- Blastomycosis (see Blastomycosis)
- Coccidioidomycosis (see Coccidioidomycosis)
- Cryptococcus Neoformans (see Cryptococcosis)
- Dematiaceous Mold (see xxxx)
- Fusarium (see Fusarium)
- Histoplasmosis (see Histoplasmosis)
- Mucor (see xxxx)
- Paracoccidioides Brasiliensis (see xxxx)
- Penicillium Marneffei (see Penicillium Marneffei)
- Sporotrichosis (see Sporotrichosis)
- Trichosporon (see xxxx)
- Proteus Mirabilis (see Proteus Mirabilis)
- Clinical Manifestations
- Emphysematous Cystitis: may occur
- Clinical Manifestations
- Pseudomonas Aeruginosa (see Pseudomonas Aeruginosa)
- Staphylococcus Aureus (see Staphylococcus Aureus)
- Mechanisms of Infection
- Ascending Infection Due to Foley Catheter
- Hematogenous Seeding (via Bacteremia)
- Clinical Manifestations
- Emphysematous Cystitis: may occur
- Mechanisms of Infection
- Staphylococcus Epidermidis (see Staphylococcus Epidermidis)
- Staphylococcus Saprophyticus (see Staphylococcus Saprophyticus)
- Streptococcus (see Streptococcus)
- Clinical Manifestations
- Emphysematous Cystitis: may occur
- Clinical Manifestations
- Ureaplasma Urealyticum (see Ureaplasma Urealyticum)
- Clinical Manifestations
- Acute Cystitis
- Acute Pyelonephritis
- Epididymitis (see Epididymitis)
- Urethritis (see Urethritis)
- Clinical Manifestations
Physiology
Route/Mechanism of Urinary Tract Infection
- Ascending Infection: in female, colonization of vaginal introitus with pathogens from fecal flora -> ascension via urethra into bladder (and ultimately to kidneys, via ureters)
- Bacteremic Seeding of Kidney: causes some cases of pyelonephritis
- Seeding of Kidneys from Bacteria Within Lymphatics: may play a role in some cases of pyelonephritis
Diagnosis
Urinalysis (see Urinalysis)
- General Comments
- Dipstick positivity for leukocyte esterase or nitrite has 75% sensitivity/82% specificity for detection of UTI: test is not helpful to rule out UTI if symptoms are consistent with UTI and dipstick is negative for both (due to low sensitivity)
- Nitrite
- Assay: dietary nitrate (normally present in the urine) is converted to nitrite by the nitrate reductase enzyme in certain Gram-negative bacteria -> results in pink color change on dipstick
- Specific Gram-negative bacteria (E Coli, Citrobacter, Klebsiella, Proteus, Serratia) possess nitrate reductase and are capable of this conversion
- Pseudomonas and Gram-positive bacteria (Enterococcus, etc) do not possess the nitrate reductase enzyme
- False-Positive: use of phenazopyridine, beet ingestion
- Specific Gram-negative bacteria (E Coli, Citrobacter, Klebsiella, Proteus, Serratia) possess nitrate reductase and are capable of this conversion
- Interpretation: positive nitrite indicates presence of the specific Gram-negative bacteria noted above
- Assay: dietary nitrate (normally present in the urine) is converted to nitrite by the nitrate reductase enzyme in certain Gram-negative bacteria -> results in pink color change on dipstick
- Leukocyte Esterase
- Assay: granulocyte leukocyte esterase catalyzes the hydrolysis of an amino acid ester to liberate 3-hydroxy-5-phenyl pyrrole! which reacts with a diazonium salt -> results in purple color change on dipstick
- Sensitivity: 75-96%/Specificity: 94-98% for >10 WBC per hpf
- Interpretation: positive nitrite indicates presence of pyuria
- Assay: granulocyte leukocyte esterase catalyzes the hydrolysis of an amino acid ester to liberate 3-hydroxy-5-phenyl pyrrole! which reacts with a diazonium salt -> results in purple color change on dipstick
- Protein: xxx
- Ketone: may be mildly positive in cases with associated dehydration and starvation ketoacidosis or with concomitant diabetic ketoacidosis
- RBC (on Microscopy): elevated RBC (microscopic or gross hematuria) may be seen
- Hematuria is Common in UTI, But Not in Urethritis or Vaginitis
- WBC (on Microscopy): >10 WBC/uL (pyuria) indicates UTI (cystitis or pyelonephritis)
- Pyuria May Be Absent in Some Cases of Pyelonephritis with Urinary Tract Obstruction
- Casts
- WBC Casts: indicate pyelonephritis
Urine Gram Stain (see Urine Culture)
- Assay: performed on spun urine
- Interpretation: should be positive if there are >100k colonies in culture (which is performed on unspun urine)
Urine Culture (see Urine Culture)
Performance of Urinary Culture in Patient with Foley Catheter (Centers for Disease Control and Prevention, CDC) [LINK]
- Appropriate Uses of Urine Culture
- Presence of Symptoms/Signs of Urinary Tract Infection (UTI)
- Acute Hematuria (see Hematuria)
- Flank Pain/Costovertebral Angle Tenderness (see Flank Pain)
- New Pelvic Discomfort/Pain
- New Onset/Worsening Sepsis Without Historical/Physical Examination/Laboratory Evidence of Another Source (see Sepsis)
- Including Any SIRS and/or SOFA/qSOFA Criteria (Altered Mental Status, Fever, Hypotension, etc)
- Presence of Unique Physiologic Features in A Patient with Spinal Cord Injury (SCI) (see Spinal Cord Injury)
- Autonomic Dysreflexia (see Autonomic Dysreflexia)
- Increased Spasticity (see Spasticity)
- Sense of Unease
- Presence of Symptoms/Signs of Urinary Tract Infection (UTI)
- Inappropriate Uses of Urine Culture
- Odorous, Cloudy, or Discolored Urine in the Absence of Other Localizing Symptoms/Sighs (as Noted Above)
- Reflex Urine Cultures Based on Urinalysis Results (Such as Pyuria) in the Absence of Other Indications
- Note: the Absence of Pyuria Suggests a Diagnosis Other than Catheter-Associated Urinary Tract Infection (CAUTI)
- Urine Culture to Routinely Document Response to Therapy (Unless Symptoms Fail to Resolve)
Assay
- Clean-Catch (in female: after cleansing of external urethra prior to collection) or via Foley Catheter
Interpretation
- *Historically considered positive if there are >100k CFU/mL in culture (this originated from literature in pregnant females with first void morning urine samples)
- However, urinary tract infection may occur with colony counts <100k CFU/mL
- Male: colony count >10k CFU/mL is considered positive
- Lower colony counts of coliforms (E Coli, etc) are likely to represent significant bacteriuria
- In some female cases with infection due to Chlamydia Trachomatis/Neisseria Gonorrhoeae/HSV, culture may be negative
Isolation of Other Organisms from Urine Culture
- Lactobacillus, Enterococcus, Staphylococcus Epidermidis and group B Streptococcus isolated from a voided urine culture in female may suggest contamination
- However, Presence of organism in midstream voided urine at high colony count and with pure growth may suggest that organism is etiologic
Abdominal/Pelvic Computed Tomography (CT) (see Abdominal-Pelvic Computed Tomography)
- Diagnostic of nephrolithiasis and hydronephrosis
- May demonstrate emphysematous pyelonephritis or emphysematous cystitis
KUB (see Kidneys-Ureters-Bladder X-Ray)
- May occasionally detect nephrolithiasis
Renal Ultrasound (see Renal Ultrasound)
- May be required to rule out hydronephrosis (due to obstruction), anatomic abnormailities, nephrolithiasis, etc
Clinical Presentations
Asymptomatic Bacteriuria
Definition
- Asymptomatic Bacteriuria is Defined as Positive Urine Culture in the Absence of Clinical Symptoms
- Male: defined as single clean-catch voided urine with single bacterial species isolated in count >100k CFU/mL in absence of symptoms
- Female: XXXXXX
Differentiation of Catheter-Associated Asymptomatic Bacteriuria (CA-ASB) vs Catheter-Associated Urinary Tract Infection (CAUTI) (Centers for Disease Control and Prevention, CDC) [LINK]
Epidemiology
- Prevalence of Male Asymptomatic Bacteriuria
- Young Male: rare
- Elderly Male: prevalence of 6%
- Prevalence of Female Asymptomatic Bacteriuria
- Young Female: xxx
- Elderly Female: prevalence of 18%
Indications to Preoperatively Screen for Asymptomatic Bacteriuria
- Other than urologic procedures, the risk of surgical site infection for other surgical procedures (including procedures with high risk of infection, like joint arthroplasty) with pre-operative asymptomatic bacteriuria probably does not warrant screening
- Pre-Trans-Urethral Resection of Prostate (TURP): due to risk of bacteremia/sepsis
- Pre-Urologic Procedures Where Mucosal Bleeding is Anticipated: due to risk of bacteremia/sepsis
Asymptomatic Candiduria (see Candida)
- xxx
Acute Cystitis
- Definition: infection of urinary bladder (lower urinary tract)
- May occur alone or in conjunction with pyelonephritis or prostatitis
- General Comments
- Males with Recurrent Cystitis: should undergo evaluation for prostatitis
- Cloudy Urine
- Dysuria (see Dysuria)
- Gross Hematuria (see Hematuria)
- Suprapubic or Low Abdominal Pain (see Abdominal Pain)
- Urinary Frequency
- Urinary Urgency
Emphysematous Cystitis
- Epidemiology: rare
- Risk Factors
- Diabetes Mellitus (see Diabetes Mellitus)
- Female Sex
- Immunocompromised State
- Neurogenic Bladder
- Prior Urinary Tract Infection
- Renal Transplant (see Renal Transplant)
- Urinary Stasis
- Specific Microbial Etiologies
- Candida Albicans (see Candida)
- Clostridium Perfringens (see Clostridium Perfringens)
- Escherichia Coli (see Escherichia Coli): most common etiology of emphysematous cystitis
- Enterobacter Aerogenes (see Enterobacter Aerogenes)
- Klebsiella Pneumoniae (see Klebsiella Pneumoniae)
- Proteus Mirabilis (see Proteus Mirabilis)
- Staphylococcus Aureus (see Staphylococcus Aureus)
- Streptococcus (see Streptococcus)
- Mechanism: gas may appear in the wall of the bladder by either transluminal dissection of gas or true infection of the bladder wall with pathogens
- Diagnosis: abdominal/pelvic CT scan
- Clinical Manifestations
- Abdominal Pain (see Abdominal Pain)
- Gas In Bladder Wall (Seen on CT Scan): due to bacterial or fungal fermentation
- Pneumaturia (see Pneumaturia): highly suggestive (although not usually noted by the patient)
- Prognosis: delayed diagnosis and treatment may result in overwhelming infection, extension to ureters and renal parenchyma, bladder rupture, and death
Acute Pyelonephritis
- Definition: infection of kidney (upper urinary tract)
- May occur alone or in conjunction with cystitis
- General Comments
- Symptoms may co-exist with those of acute cystitis
- Abdominal Pain (see Abdominal Pain)
- Costovertebral Angle Tenderness
- Fever/Chills (see Fever)
- Flank Pain (see Flank Pain): present in cases with pyelonephritis
- Diarrhea (see Diarrhea)
- Nausea and Vomiting (see Nausea and Vomiting)
Emphysematous Pyelonephritis
- Risk Factors
- Diabetes Mellitus with Escherichia Coli Urinary Tract Infection (see Escherichia Coli)
- Diabetes Mellitus with Klebsiella Pneumoniae Urinary Tract Infection (see Klebsiella Pneumoniae)
- Staging (Huang and Tseng, 2000)
- Class 1: gas confined to the collecting system
- Class 2: gas confined to the renal parenchyma alone
- Class 3A: perinephric extension of gas or abscess
- Class 3B: extension of gas beyond the Gerota fascia
- Class 4: bilateral emphysematous pyelonephritis or pyelonephritis in a solitary kidney
- Diagnosis : abdominal/pelvic CT scan
- Clinical Manifestations
- Pyelonephritis with Gas Accumulation in Kidney
- Pneumomediastinum (see Pneumomediastinum): case reports
- Subcutaneous Emphysema (see Subcutaneous Emphysema): case reports
- Prognosis: may be fatal, if not rapidly treated
Complications
- Acute Kidney Injury (AKI) (see Acute Kidney Injury)
- Peri-Nephric Abscess (see Peri-Nephric Abscess)
- Renal Abscess (see Renal Abscess)
- Sepsis (see Sepsis)
Prevention
Measures Which Do Not Have Demonstrated Clinical Efficacy
- Chlorhexidine Gluconate Skin Decontamination (see Chlorhexidine Gluconate)
- Clinical Efficacy
- Randomized Trial of Daily Chlorhexidine Bathing to Prevent Healthcare-Associated Infections ( JAMA, 2015) [MEDLINE]
- Daily Chlorhexidine Gluconate Bathing Did Not Decrease the Incidence of Healthcare-Associated Infections (Central Line-Associated Bloodstream Infections, Catheter-Related Urinary Tract Infection, Ventilator-Associated Pneumonia, or Clostridium Difficile)
- Randomized Trial of Daily Chlorhexidine Bathing to Prevent Healthcare-Associated Infections ( JAMA, 2015) [MEDLINE]
- Clinical Efficacy
Treatment
Acute Cystitis
Oral (PO) Antibiotics
- Amoxicillin (see Amoxicillin)
- Resistance rates are typically >20% in most regions -> avoid empiric use
- Amoxicillin-Clavulanic Acid (Augmentin) (ee Amoxicillin-Clavulanic Acid)/First and Second-Generation Cephalosporins (Cefpodoxime, Cefaclor, Cefdinir) (see Cephalosporins)
- Resistance rates are <10% in most regions -> acceptable for empiric use for female cystitis (7 day regimen)
- Fluoroquinolone (see Fluoroquinolones)
- General Comments
- Clinical Efficacy: effective for female cystitis (3 day regimen)
- However, should probably be reserved for more serious conditions than acute cystitis (due to concerns about increasing resistance to these agents)
- Agents
- Ciprofloxacin (Cipro) (see Ciprofloxacin)
- Levofloxacin (Levaquin) (see Levofloxacin)
- Ofloxacin (see Ofloxacin)
- General Comments
- Fosfomycin
- Female Cystitis: 91% clinical efficacy (single dose)
- Male Cystitis: data for use in male UTI is limited
- Avoid use if early pyelonephritis is suspected (due to inadequate renal tissue levels)
- Nitrofurantoin (Macrodantin) (see Nitrofurantoin)
- Female Cystitis: 90-95% clinical efficacy (5-7 day course), but may be inferior to other first-line agents
- Male Cystitis: contraindicated, as agent is less effective for occult prostatitis
- Contraindication: creatinine clearance <60 mL/min
- Avoid use if early pyelonephritis is suspected (due to inadequate renal tissue levels)
- Trimethoprim-Sulfamethoxazole (Bactrim) (see Sulfamethoxazole-Trimethoprim)
- Female Cystitis: 86-100% clinical efficacy (3-7 day course)
- Avoid empiric use of this agent if community urinary tract pathogen resistance is >20% (>20% threshold is based on mathematical models)
- Risk Factors for Trimethoprim-Sulfamethoxazole Resistance
- Use of Trimethoprim-Sulfamethoxazole in Prior 3-6 mo
- Foreign Travel (Especially International Travel)
Intravenous (IV) Antibiotics (usually not required for acute cystitis, unless concomitant acute pyelonephritis is present)
- Ampicillin (see Ampicillin)
- Resistance rates are typically >20% in most regions -> avoid empiric use
- Fluoroquinolone (see Fluoroquinolones)
- Agents
- Ciprofloxacin (Cipro) (see Ciprofloxacin)
- Levofloxacin (Levaquin) (see Levofloxacin)
- Agents
Clinical Guidelines for Short-Course Antibiotics in Common Infections (Annals of Internal Medicine, 2021) [MEDLINE]
- In women with uncomplicated bac- terial cystitis, clinicians should prescribe short-course antibi- otics with either nitrofurantoin for 5 days, trimethoprim– sulfamethoxazole (TMP–SMZ) for 3 days, or fosfomycin as a single dose
- In men and women with uncomplicated pyelo- nephritis, clinicians should prescribe short-course therapy either with fluoroquinolones (5 to 7 days) or TMP–SMZ (14 days) based on antibiotic susceptibility
Emphysematous Cystitis
- Intravenous Antibiotics
- Bladder Drainage
Acute Pyelonephritis
Oral (PO) Antibiotics
- Amoxicillin-Clavulanic Acid (Augmentin) (ee Amoxicillin-Clavulanic Acid)/Second or Third-Generation Cephalosporins (Cefpodoxime, Cefaclor, Cefdinir) (see Cephalosporins)
- Less effective for treatment of pyelonephritis
- However, if pathogen is known to be susceptible, need to use at least a 14 day regimen
- Fluoroquinolone (see Fluoroquinolones): fluoroquinolones are the only recommended outpatient PO treatment for pyelonephritis
- Agents
- Ciprofloxacin (Cipro) (see Ciprofloxacin)
- Levofloxacin (Levaquin) (see Levofloxacin)
- Ofloxacin (see Ofloxacin)
- Agents
Intravenous (IV) Antibiotics
- Aminoglycoside (see Aminoglycosides)
- Gentamicin (see Gentamicin)
- Tobramycin (see Tobramycin)
- Aztreonam (see Aztreonam)
- Carbapenem (see Carbapenems): may be used for pyelonephritis (especially cases due to extended-spectrum beta-lactamase (ESBL)-producing strains)
- Extended-Spectrum/Anti-Pseudomonal Cephalosporin (see Cephalosporins)
- Cefepime (Maxipime) (see Cefepime)
- Cefoperazone (Cefobid) (see Cefoperazone)
- Ceftazidime (Ceftaz) (see Ceftazidime)
- Extended-Spectrum/Anti-Pseudomonal Penicillin
- Piperacillin-Tazobactam (Zosyn) (see Piperacillin-Tazobactam)
- Fluoroquinolone (see Fluoroquinolones): commonly used
- Agents
- Ciprofloxacin (Cipro) (see Ciprofloxacin)
- Levofloxacin (Levaquin) (see Levofloxacin)
- Agents
- Third-Generation Cephalosporin (see Cephalosporins)
- Ceftriaxone (Rocephin) (see Ceftriaxone)
Emphysematous Pylelonephritis
- Intravenous Antibiotics
- Nephrectomy (see Nephrectomy): may be required
Treatment Duration
- Male Treatment Duration
- Cystitis: 7 days is generally adequate
- Persistent or recurrent symptoms despite treatment indicate need for evaluation for possible prostatitis
- Pyelonephritis: presence of bacteremia with pyelonephritis does not mandate longer antibiotic course (assuming no other complicating factors)
- Cystitis: 7 days is generally adequate
- Female Treatment Duration
- Cystitis: some agents can be used in 3-day course, although most courses are 7 days
- Pyelonephritis: presence of bacteremia with pyelonephritis does not mandate longer antibiotic course (assuming no other complicating factors)
Urinary Tract Analgesic
- Phenazopyridine (Pyridium) (see Phenazopyridine)
Treatment of Pre-Operative Asymptomatic Bacteriuria
- Treatment of pre-operative asymptomatic bacteriuria does not decrease the risk of subsequent UTI or risk of surgical wound infection
Treatment of Pre-Operative Symptomatic Urinary Tract Infection
- Indicated
Management of Staphylococcus Aureus Bacteriuria
- In Presence of Foley Catheter (see Foley Catheter): in absence of systemic signs of infection, work-up for bacteremia is not necessary
- In Absence of Foley Catheter: may be indicative of bacteremia, therefore, work-up for bacteremia is required
Management of Candiduria
- See Candida
Prognosis
- Presence of Bacteremia with Pyelonephritis: does not confer a worse prognosis
References
- Emphysematous pyelonephritis: clinicoradiological classification, management, prognosis, and pathogenesis. Arch Intern Med. Mar 27 2000;160(6):797-805 [MEDLINE]
- Emphysematous cystitis: An unusual disease of the Genito-Urinary system suspected on imaging. Ann Clin Microbiol Antimicrob. 2004; 3: 20 [MEDLINE]
- Chlorhexidine bathing and health care-associated infections: a randomized clinical trial. JAMA. 2015 Jan 27;313(4):369-78. doi: 10.1001/jama.2014.18400 [MEDLINE]
- Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Apr 6. doi: 10.7326/M20-7355 [MEDLINE]