Urinary Tract Infections

Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Depending on the location of the infection, patients can present with dysuria, urinary urgency, increased urinary frequency, suprapubic pain, and fever. Urinalysis and urine culture along with the clinical presentation help in the diagnosis of UTIs. Management options include oral or IV antibiotics such as trimethoprim-sulfamethoxazole, nitrofurantoin, and ceftriaxone. In certain instances, further workup may be needed to determine the underlying conditions that predispose an individual to UTIs.

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Overview

Definition

Urinary tract infection (UTI) is a pathogenic process that develops when a microorganism (usually bacteria) enters the body through the urethra and travels to the bladder and/or kidneys.

Epidemiology

Prevalence:

  • Asymptomatic bacteriuria (bacteria in the urine):
    • 1%–5% of non-pregnant, premenopausal women
    • 1.5%–9.8% of pregnant women
    • 2.8%–8.6% of postmenopausal women
  • Uncomplicated cystitis:
    • Up to 60% of women may have ≥ 1 UTI at some time.
    • Up to 10% of women have ≥ 1 UTI each year.
    • Approximately 2%–5% of women have recurrent UTI.
    • Most common in sexually active, 18–24-year-old women
  • Men:
    • < 0.1% overall
    • ↑ Risk if uncircumcised or in case of anal-insertive intercourse

Risk factors

  • Women > men: 
    • Short urethra predisposes all women:
      • Less distance for bacteria to ascend to the bladder
      • Less time for micturition to wash away ascending bacteria in the urethra
    • Additional risk factors are usually needed for UTIs to occur in men.
  • Comorbidities:
    • Immunocompromised state
    • Diabetes (glucosuria provides a food source for bacteria)
    • History of UTIs
  • Behavioral:
    • Poor hygiene and fecal incontinence (↑ genital/periurethral colonization)
    • Sexual intercourse:
      • Facilitates bacterial infections in women
      • Anal-insertive intercourse may result in bacterial infections in men.
  • Anatomical (causes of urinary stasis/obstruction):
    • Posterior urethral valves → ureteral reflux → pyelonephritis
    • Benign prostatic hyperplasia (BPH)
    • Urethral stricture
    • Cystocele
    • Neurogenic bladder
    • Nephrolithiasis
  • Foreign body (nidus for infection and/or allows entry into body):
    • Foley catheter
    • Suprapubic catheter
    • Ureteral stent
    • Urologic instrumentation (i.e., cystoscopy)
  • Medications:
    • Anticholinergics (i.e., diphenhydramine):
      • Can cause incomplete emptying of the bladder
      • Elderly primarily affected
    • Antibiotics (frequent use = ↑ resistance)

Etiology and Pathophysiology

Escherichia coli

  • 75%–95% of all UTIs due to uropathogenic E. coli
  • Virulence factors aid in colonization, ascension, and invasion of the urinary tract:
    • Type 1 fimbriae (in mannose-sensitive E. coli) of bacterium:
      • Attach to the uroepithelial cells (on the mannose residues of surface glycoproteins)
      • Prevent E. coli from being flushed out by the urine stream
    • P fimbriae: 
      • Hair-like projections that interact with renal epithelial cells
      • Important role in pyelonephritis
  • Uromodulin (human defense factor), which has mannose residues, prevents E. coli from binding to the uroepithelial cells.

Other bacteria

Non-E. coli bacteria are associated with risk factors for drug resistance or in specific clinical scenarios.

  • Urease-producing bacteria:
    • Associated with ↑ risk of staghorn kidney stones
    • Alkaline urine → ↓ solubility of phosphate → precipitation of magnesium ammonium phosphate (struvite) → staghorn kidney stones
    •  Proteus mirabilis and Ureaplasma urealyticum
    • Klebsiella pneumoniae: associated with hospital-acquired infections
    • Staphylococcus saprophyticus: associated with UTIs in women following sexual intercourse
  • Enterococci (i.e., Enterococcus faecalis): 
    • Can cause true infections or can be a contaminant (i.e., from feces)
    • Associated with hospital-acquired infections

Fungi and viruses

  • Fungi:
    • Candida: most common cause of fungal UTIs
    • Seen in hospitalized patients (↑ risk with indwelling catheters)
    • Treatment (fluconazole or amphotericin) is not required if asymptomatic (i.e., colonization only).
  • Viruses:
    • Rare cause (adenovirus, JC/BK polyomavirus)
    • In the setting of extreme immunosuppression (i.e., patients who have undergone a transplant)
    • Presentation (i.e., hemorrhagic cystitis) is not that of a classic UTI.

Infectious process

  • Initial invasion to urethritis:
    • Contamination of the periurethral area → colonization of the urethra + migration to the bladder
    • Development of urethritis
  • Once in the bladder:
    • Colonization → invasion + inflammation of the bladder → accumulation of fibrinogen
    • At this stage, the patient presents with cystitis.
  • Neutrophil infiltration and immune response:
    • Bacteria start multiplying → neutrophils infiltrate the urinary bladder → systemic immune reaction
    • Accompanied by leukocytosis and systemic symptoms and signs
  • A biofilm is formed and the uroepithelial surface of the ureters is extensively damaged by bacterial toxins and proteases.
  • Bacterial organisms ascend to the kidneys → pyelonephritis

Clinical Presentation

Characteristic features

  • Dysuria + bacteriuria
  • UTIs can be:
    • Uncomplicated:
      • UTIs of the lower urinary tract
      • No associated systemic symptoms
    • Complicated:
      • UTIs extending beyond the bladder (kidney/upper urinary tract)
      • Accompanied by systemic symptoms (i.e., fever, sepsis, altered mental status)
  • Other considerations:
    • Historically, the following situations were considered complicated UTIs automatically:
      • UTIs in men
      • Immunocompromised (including diabetics) individuals
      • Urologic abnormalities (i.e., kidney stones and ureteral stents)
    • Antibiotic stewardship (i.e., concern for antibiotic resistance due to overuse) has shifted the trend:
      • If the patient is stable or without systemic symptoms, treat as an outpatient. 
      • Monitor these patients (listed above) with awareness of their increased risk for serious infections.

Uncomplicated UTIs

  • Also known as “simple UTI,” “simple cystitis,” or “uncomplicated cystitis”
  • Almost exclusively in women (possible, but rare in men)
  • UTI of the lower urinary tract (cystitis):
    • Painful urination (dysuria)
    • Sensation of needing to urinate immediately (urgency)
    • Increased frequency of urination (frequency)
    • Suprapubic abdominal pain
  •  The patient has:
    • No systemic symptoms
    • No signs of pyelonephritis (flank pain, costovertebral angle tenderness)
    • No suspicious symptoms of:
      • STIs (urethritis, pelvic inflammatory disease (PID), urethral/vaginal discharge, dyspareunia)
      • Prostatitis (perineal pain, prostatic pain, urethral discharge)
  • Symptoms may be more vague in the elderly.

Complicated UTIs

  • Pyelonephritis:
    • UTI of the upper urinary tract (i.e., kidneys)
    • Most are pyelonephritis (some use the terms interchangeably).
    • Characteristic symptoms:
      • Fever, chills, rigors
      • Flank pain
      • Costovertebral angle tenderness
    • Symptoms of cystitis may or may not be present.
  • Complicated cystitis:
    • Patients are often febrile or show sepsis
    • No signs of pyelonephritis
    • Without any other identified sources of infection

Diagnosis

Diagnostic approach

  • History: risk factors and characteristic symptoms
  • Test: Check for the presence of bacteria in urine (identified based on urinalysis and culture).
  • Categorization: determines additional workup and treatment

Urinalysis

  • Normal urine:
    • Sterile (i.e., no normal flora)
    • Without WBCs
  • Proper urine-collection technique:
    • Urogenital area frequently colonized → ↑ risk for contamination
    • Minimize risk of contamination via:
      • Cleansing of genitals and urethra prior to collection
      • Midstream urine collection (i.e., discard initial volume of urine)
    • Option in infants and toddlers in diapers: straight catheterization of the urethra
  • Pyuria is a marker for bacteriuria:
    • Microscopy: ≥ 10 leukocytes/µL → clinically significant pyuria
    • Detectable before results of Gram stain and culture:
      • Very sensitive for UTIs
      • Consider alternative diagnoses if pyuria is absent.
      • Pyuria + characteristic symptoms → may proceed with empiric treatment
  • Leukocyte esterase and nitrite:
    • Leukocyte esterase: 
      • Enzyme released from WBCs
      • Sensitive and specific for UTIs
    • Nitrite: 
      • Reflects + Enterobacteriaceae (i.e., E. coli), which has the bacterial enzyme that converts dietary nitrates to nitrites
      • Index of bacteriuria (can be negative if incubation time in the bladder is insufficient to convert nitrate to nitrite)
  • Other markers of UTIs:
    • Microscopic hematuria:
      • RBCs enter the urine due to local tissue inflammation.
      • Repeat urinalysis after treatment (to ensure there are no other serious causes of hematuria).
      • Non-UTI causes: bladder tumors, glomerulonephritis, and kidney stones
    • Alkaline urine:
      • Urine pH > 7: consistent with urease-producing bacteria
      • Not sufficient alone to make diagnosis
  • Other considerations:
    • Point of care (i.e., dipstick) urinalysis:
      • Performed in an outpatient setting
      • May be used alone in classic uncomplicated cystitis in women
      • Provides information on Leukocyte esterase and nitrite
      • No quantitative information on urine WBC count
      • Performed when there is no opportunity for urine culture
    • Lab-based urinalysis:
      • In outpatient or inpatient settings
      • Provides quantitative information on urine WBC count
      • Urine culture is often “reflexed” if pyuria is present.

Urine culture

  • Multiple organisms growing simultaneously is suggestive of contamination.
  • Common contaminants: 
    • Lactobacilli
    • Enterococci
    • Group-B streptococci
    • Coagulase-negative staphylococci (other than S. saprophyticus)
  • Gram staining:
    • Available prior to culture results and can guide therapy
    • Identifies possible contaminants (i.e., not true UTIs)
  • Quantitative bacterial count:
    • ≥ 105 colony forming units (CFUs)/mL reflect bladder bacteriuria:
      • A high threshold helps differentiate from contamination.
      • The urine culture may be repeated to ensure that bacterial counts are consistent.
    • ≥ 102 CFUs/mL: adequate, if characteristic symptoms of UTI are present
  • Not necessary in uncomplicated cystitis in non-pregnant women

Categorization

  • Categories considered before diagnosing uncomplicated cystitis and determining further workup:
    • Pregnancy:
      • Pregnancy test for all women of child-bearing age
      • Requires avoidance of teratogenic antibiotics
    • Indwelling catheters (Foley, suprapubic catheter): consider removal
    • Men:
      • Overall, UTIs are rare.
      • Often need a further workup (i.e., imaging, urology consult) to determine the possible anatomic cause of the UTI
    • Kidney transplant:
      • Different microorganisms may be present (including JC/BK virus).
      • Consider nephrology and/or infectious disease consults.
    • Recurrent UTI:
      • Requires a thorough review of past culture results
      • Consider an infectious disease consult.
    • Genitourinary features (i.e., vaginal discharge):
      • Rule out STIs (i.e., gonorrhea, chlamydia).
      • Pelvic exam
  • Complicated UTIs:
    • May require admission and IV antibiotics
    • May require diagnostic imaging (ultrasound or CT scan):
      • Urinary tract obstruction (i.e., tumors, BPH)
      • Kidney stones (nidus for infection)
      • Retained ureteral stent (nidus for infection)
      • Perinephric abscess
  • Assessment of possible multi-drug resistant (MDR) bacteria:
    • Risk factors: 
      • Recent antibiotic use
      • Recent high-risk travel
      • Previous MDR bacteria on urine culture
      • Recent hospitalization or nursing-home stay
    • May require different antibiotics and closer monitoring even if with uncomplicated cystitis
CT scan showing the left renal stone

A CT scan showing left renal stone

Image: “Surgical Clips Migration up to Renal Collecting System from Ileal Conduit Postcystectomy” by Journal of Endourology Case Reports. License: CC BY 4.0
Ultrasound showing renal abscess

Ultrasound showing a renal abscess that appears as a hypoechoic area measuring 1.19 × 0.96 cm within the cortex of the left kidney

Image: “Transient Monoclonal Gammopathy Induced by Disseminated Staphylococcus aureus Infection” by Stoimenis D, Spyridonidou C, Papaioannou N. License: CC BY 3.0

Management

Treatment approach

  • Antibiotics:
    • Choose antibiotics depending on culture sensitivities (if possible).
    • Minimize fluoroquinolone use:
      • Spectrum is too broad for uncomplicated UTIs.
      • Emergent antibiotic resistance
      • Many side effects (i.e., tendon rupture)
  • Relieve obstruction, if present:
    • Foley catheter for bladder outlet obstruction (i.e., BPH)
    • Urologic intervention for nephrolithiasis, ureteral obstruction, or perinephric abscess
    • Gynecological intervention for pelvic tumors
  • Reassessment needed:
    • If an uncomplicated UTI does not improve after 48 hours of commencement of antibiotics:
      • The patient may actually have a complicated UTI.
      • Additional imaging may be needed to determine obstruction/abscess.
    • If hematuria (nonspecific for UTIs) was found on initial urinalysis:
      • Repeat urinalysis after completion of treatment.
      • Do not want to miss coincidental occult bladder cancer
Table: Antibiotics
Type of UTIAntibiotics
Uncomplicated UTI (simple cystitis)
  • Nitrofurantoin
  • Trimethoprim-sulfamethoxazole
  • Fosfomycin
  • Pivmecillinam (not available in the United States)
Complicated UTI (including pyelonephritis)
  • Outpatient: oral ciprofloxacin or levofloxacin
  • Inpatient options:
    • No risk factors for multi-drug resistance:
      • IV ceftriaxone
      • IV piperacillin-tazobactam
      • IV ciprofloxacin/levofloxacin
    • With risk factors for multi-drug resistance:
      • IV piperacillin-tazobactam
      • IV carbepenem (meropenem/imipenem/doripenem)
    • Critically ill: IV carbepenem plus IV vancomycin
UTI: urinary tract infection

Special Cases

The following patient populations may require a different standard of care, as they do not fall into the usual categories of UTIs:

Pregnancy

  • ↑ Risk of UTIs due to physiological changes:
    • Urinary stasis (progesterone inhibits contraction of smooth muscles)
    • Ureteral smooth muscle relaxation and dilation 
    • ↑ Pressure on the bladder from the uterus
    • Immunosuppression
  • Obstetric outcomes associated with UTIs:
    • Preterm birth
    • Low birth weight
    • ↑ Perinatal mortality
  • Asymptomatic bacteriuria:
    • Approximately ⅓ of cases progress to UTIs. 
    • Screening: at approximately 12–16 weeks of gestation
    • Treat if found, and obtain a follow-up urine culture.
  • Antibiotics:
    • Amoxicillin-clavulanic acid, cephalexin, fosfomycin
    • Do not use in the 1st trimester or at term:
      • Trimethoprim-sulfamethoxazole
      • Nitrofurantoin
    • Avoid fluoroquinolones.
  • Treat complicated UTIs (i.e., pyelonephritis) aggressively:
    • Due to association with worse obstetric outcomes
    • Usually requires hospitalization and IV antibiotics
  • Post-treatment urine culture is always ordered to ensure eradication.

Asymptomatic bacteriuria

  • Bacteriuria (≥ 105 CFUs/mL) without characteristic symptoms of UTIs
  • Often found incidentally and treated unnecessarily
  • Usually do not require treatment, unless:
    • Pregnant
    • Recent kidney transplant
    • With planned urologic procedure (risk for seeding the bloodstream)

Catheter-associated UTI (CAUTI)

  • Characterized by:
    • Bacteriuria (from urine sample obtained midstream or newly replaced catheter)
    • Indwelling urinary catheter (or removed within 48 hours)
    • Symptoms attributable to infection 
  • Presentation and considerations:
    • Patients will often not exhibit classic dysuria/urgency/frequency:
      • Characteristic symptoms blunted by urinary catheter
      • Systemic symptoms (fever, costovertebral angle tenderness, sepsis) are helpful in diagnosis.
    • All catheters will eventually become colonized with bacteria.
    • Treating asymptomatic bacteriuria in catheterized patients does not improve outcomes.
  • Management:
    • Removal and replacement of the catheter
    • May require switching to intermittent straight catheterization

Kidney transplant

  • Consider additional pathogens due to the suppressed immune system.
  • Presentation:
    • Classic symptoms of UTI with common organisms (i.e., E. coli)
    • Hemorrhagic cystitis (due to BK/JC virus)
  • Ensure that antibiotics do not interfere with transplant medications.

Recurrent UTIs

  • Characterized by:
    • ≥ 2 UTIs in 6 months or ≥ 3 UTIs in 1 year
    • Usually uncomplicated UTIs (i.e., simple cystitis)
    • Usually reinfection (more common) and not relapse, even if the same organism is found repeatedly
  • Risk factors: 
    • Anatomical urologic abnormalities
    • Sexual intercourse
    • Spermicide use
  • Evaluate for reinfection versus relapse: 
    • Reinfection (new infection after adequate treatment): 
      • True even if same organism is found again after 2 weeks of treatment
      • Relatively common for uncomplicated cystitis in women
    • Relapse (inadequate initial treatment):
      • The same organism colonizes within 2 weeks of treatment.
      • Imaging to screen for anatomical problems (especially if accompanied by hematuria, Proteus infection due to ↑ risk of struvite stones)
  • Treatment: same as that use for isolated cases of UTI
  • Prevention:
    • Increase oral fluid intake.
    • Post-coital voiding
    • Avoid spermicides.
    • Minimize fecal contamination by wiping front to back.
    • Topical estrogen in post-menopausal women (promotes healthy vaginal flora)
    • Consider prophylactic antibiotics (daily versus post-coital).

Differential Diagnosis

  • Vaginitis: a vaginal infection (bacterial vaginosis, trichomoniasis, candidiasis) that may present with dysuria. Signs that are not found in UTIs may be present, including odor, vaginal discharge, and pruritus. Urinalysis may show pyuria; however, hematuria will not be present. Treatment depends on etiology (often metronidazole or fluconazole).
  • PID: an infection of the uterus, fallopian tubes, and/or ovaries that can present with suprapubic abdominal pain similar to that experienced in a UTI. Sexual intercourse is a major risk factor, as the etiology is an STI (i.e., gonorrhea, chlamydia). Inadequately treated PID can cause infertility; thus, the diagnosis of PID must always be considered in a sexually active woman with UTI. Treatment is with broad-spectrum IV antibiotics.
  • Prostatitis: an acute or chronic prostate infection that presents with dysuria, perineal pain, and voiding difficulties. Since the prostate gland drains into the urine, pyuria and a positive urine culture can be expected. Similar bacteria plus gonorrhea and chlamydia cause prostatitis. Examination reveals a very tender prostate (gentle exam only, to avoid the risk of inducing bacteremia). Patients with acute prostatitis are usually very ill and present with signs similar to those seen in complicated UTI/pyelonephritis. Chronic prostatitis is often mistaken as recurrent UTI. Treatment is using antibiotics, with coverage for gonorrhea and chlamydia, if suspected.
  • Urethritis: an STI of the urethra (usually gonorrhea and/or chlamydia) that presents with dysuria and purulent urethral discharge. Diagnosis is made by Gram stain of the urethral discharge and testing for gonorrhea and chlamydia. Urinalysis will show pyuria, but the urine culture will be negative (“sterile pyuria”). Treatment options include ceftriaxone (for gonorrhea) and azithromycin or doxycycline (for chlamydia). As coinfection with chlamydia is common, both conditions are treated simultaneously even if only gonorrhea is isolated on testing.
  • Interstitial cystitis (“bladder pain syndrome”): noninfectious, chronic (> 6 weeks) bladder pain with an unknown etiology. Interstitial cystitis may present similarly to a UTI; however, the urine culture will be negative. Management includes supportive care for pain control and certain urologic procedures. Overall, interstitial cystitis is difficult to treat.

References

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  3. Cox, G.M., Kauffman, C.A. (2020). Candida infections of the bladder and kidneys. UpToDate. Retrieved March 23, 2021, from https://www.uptodate.com/contents/candida-infections-of-the-bladder-and-kidneys
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