Enterobacteriaceae: Proteus

Proteus spp. are gram-negative, facultatively anaerobic bacilli. Different types of infection result from Proteus, but the urinary tract is the most common site. The majority of cases are caused by Proteus mirabilis (P. mirabilis). The bacteria are part of the normal intestinal flora and are also found in the environment. Proteus spp. exhibit a characteristic swarming motility and strong urease activity, which enable initiation of infection. Hydrolysis of urea by urease leads to alkaline urine with an ammonia-like odor. With the elevated pH in the urine, struvite renal stones form, which eventually can cause obstruction and renal failure. Treatment is with antibiotics (e.g., trimethoprim-sulfamethoxazole) for the infection and surgical removal of the stones, if present.

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Classification

Gram-negative bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thin layer of peptidoglycan do not retain the crystal violet stain utilized in Gram staining. These bacteria do, however, retain the safranin counterstain and thus appear as pinkish-red on the stain, making them gram negative. These bacteria can be further classified according to morphology (diplococci, curved rods, bacilli, and coccobacilli) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The bacteria can be more narrowly identified by growing them on specific media (triple sugar iron (TSI) agar) where their enzymes can be identified (urease, oxidase) and their ability to ferment lactose can be tested.
* Stains poorly on Gram stain
** Pleomorphic rod/coccobacillus
*** Require special transport media

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General Characteristics

Proteus spp.

  • Structure: bacilli
  • Gram stain: gram negative
  • Oxygen requirement: facultative anaerobic
  • Lactose fermentation: Non-lactose fermenting
  • Enzymes or biochemical test(s):
    • Oxidase negative
    • Strong urease activity
    • Indole: positive in Proteus vulgaris (P. vulgaris); negative in P. mirabilis
  • Swarming motility (organism’s motility has a spreading effect over the blood agar plate) 
  • Produce H2S (hydrogen sulfide) on triple sugar iron (TSI) agar
  • Associated diseases:
    • Urinary tract infection (UTI)
    • Soft tissue infection
    • Intra-abdominal infection

Clinically relevant species

  • P. mirabilis 
  • P. vulgaris

Epidemiology

  • P. mirabilis: etiology for 90% of Proteus infections, most commonly UTI
  • Proteus UTI:
    • 5% of hospital-acquired UTIs 
    • 10%–15% of complicated infections (especially catheter-associated UTI) 
  • P. mirabilis infections can be acquired in the community, while the rest are mostly from hospitals and long-term care facilities.

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Pathogenesis

Reservoir and transmission

  • Reservoir:
    • Normal flora of the human intestinal tract
    • Environment (soil and water)
  • Transmission: spread to the urinary tract via fecal contamination

Virulence factors

  • Fimbriae or pili:
    • Surface projections that enable attachment to host tissue
    • Initiates release of interleukins
  • Motility of Proteus (“swarm cell differentiation”):
    • Long flagella forms
    • Facilitates invasion of the urinary tract
  • Urease: 
    • Results in hydrolysis of urea, releasing ammonia
    • Urine becomes alkaline, which leads to the formation of:
      • Struvite (magnesium ammonium phosphate) and carbonate–apatite crystals
      • Biofilms on catheters
      • Calculi/stones
  • Endotoxin:
    • Component of the cell wall
    • On invasion of the bloodstream, triggers an inflammatory response in sepsis

Disease process

  • UTI and renal stones:
    • Risk factors for infection: 
      • Colonization of the vagina
      • Urinary catheters
      • Urinary tract abnormalities (strictures, valves, and stones)
    • Persistent infection → ↑ ammonia production → stone formation
    • Staghorn calculi develop in the renal pelvis → obstruction → renal failure
    • Calculi also serve as the nidus for recurrent infections.
  • Other infections:
    • Bacteremia developing commonly from a UTI
    • Surgical site/soft tissue infection (decubitus and diabetic ulcers) and osteomyelitis (from a contiguous site)
    • Pneumonia (in long-term care and hospital settings)
    • Intra-abdominal abscesses
    • Neonatal meningitis (often coming from the umbilicus)

Pathogenesis of Proteus infection
The bacteria increase urine pH by enhancing urease activity. Urease metabolizes urea into ammonia and carbon dioxide. These byproducts increase the pH of the urine, predisposing the patient to struvite stone formation. The stone and bacterial infection lead to uroepithelial damage.

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Clinical Presentation

  • Urinary tract infections:
    • Urine may have an ammonia-like odor.
    • Dysuria, pyuria, suprapubic pain, and urinary frequency
    • If with pyelonephritis, symptoms may include fever, flank pain, nausea, and/or vomiting
  • Renal calculi: 
    • Small stones may be asymptomatic.
    • Fever, flank pain, hematuria in stones complicated with infection
  • Bacteremia:
    • Fever, chills, abdominal/flank pain with UTI symptoms
    • Tachycardia, hypotension in severe cases
  • Skin and soft tissue infections: open wound(s) or ulcers, signs of cellulitis

Diagnosis and Management

Diagnosis

  • Specimen dictated by localization of disease:
    • Urine
    • Blood 
    • Pus
  • Gram-stained smear and culture:
    • “Swarming” (spreading) effect over the blood agar plate 
    • Non–lactose-fermenting colonies on eosin–methylene blue (EMB) or MacConkey’s agar 
    • Production of H2S on TSI agar
  • Other laboratory studies:
    • Urinalysis: 
      • Alkaline urine
      • Positive leukocyte esterase, nitrite 
      • Microscopic bacteriuria
      • Pyuria
    • Complete blood count: may show leukocytosis
    • Creatinine: abnormal in chronic obstruction, causing renal failure
  • Imaging studies:
    • Abdominal X-ray: shows renal stones
    • Ultrasound and computed tomography (CT) scan: 
      • Detects stones and renal changes (e.g., abscess, hydronephrosis)
      • Obtained if the infection does not respond to initial treatment

Treatment

  • Antibiotics for the infection:
    • Proteus spp.: naturally resistant to nitrofurantoin
    • Options:
      • Trimethoprim-sulfamethoxazole, quinolone, cephalosporin
      • Broad coverage and longer course of treatment in complicated UTI
    • Adjust regimen based on susceptibility testing.
  • Surgical management for renal stones:
    • Struvite renal stones from a Proteus infection must be removed. 
    • Prevents severe clinical outcomes (e.g., renal failure) 
    • Eliminates sources of recurrent infection

Comparison with UTI-associated bacteria

Escherichia coli (E. coli) and Proteus spp. are common etiologies of urinary tract infection.

Table: Different factors of Proteus spp. versus E. coli
Proteus spp.E. coli
CharacteristicsGram-negative bacilliGram-negative bacilli
HabitatIntestinal tractIntestinal tract
Lactose fermentationNon-lactose fermentingLactose fermenting
IndoleP. mirabilis: negative P. vulgaris: positivePositive
TSI agarProduce H2SDoes not produce H2S
InfectionUTIMost common cause of UTI

Clinical Relevance

  • Acute pyelonephritis: infection of the renal pelvis with the involvement of the renal parenchyma. Ascending infection with E. coli is by far the most common cause, but Proteus spp. cystitis can also lead to pyelonephritis. Typical symptoms are flank pain, fever, and chills with dysuria. Management is with antibiotics.
  • Xanthogranulomatous pyelonephritis: chronic pyelonephritis that develops commonly from renal obstruction due to infected stones. Xanthogranulomatous pyelonephritis is associated with granulomatous tissue with lipid-laden macrophages, which destroy the affected kidney, and can occur in Proteus infection as well as in infection with other UTI-causing bacteria.
  • Acute prostatitis: infection of the prostate gland. Escherichia coli and Proteus spp. are among the causative agents. Patients have fever, chills, dysuria, perineal pain, and, in severe cases, urinary retention. Digital rectal examination shows a swollen, tender prostate and urinalysis indicates infection. Treatment is with antibiotics.
  • Nephrolithiasis: Proteus infection is associated with struvite stones, which form in alkaline urine. Other stone compositions include uric acid crystals, calcium phosphate or oxalate crystals, and cystine crystals. Most stones contain calcium. Stone analysis helps differentiate the composition, because this helps determine related diseases contributing to lithiasis.

References

  1. Levinson, W., Chin-Hong, P., Joyce, E.A., Nussbaum, J., & Schwartz, B. (Eds.) (2020). Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16th ed. McGraw-Hill. 
  2. Mazudamer, S. (2020). Proteus infections. Medscape. https://emedicine.medscape.com/article/226434-overview
  3. Riedel, S., et al. (Ed.) (2019). Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28th ed. McGraw-Hill.
  4. Russo, T.A., & Johnson, J.R. (2018). Diseases caused by gram-negative enteric bacilli. Jameson J, et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.

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