Continuing Education Activity

Proteus mirabilis is a gram-negative facultative anaerobe with swarming motility and an ability to self-elongate and secrete a polysaccharide which allows it to attach to and move along surfaces like catheters, intravenous lines, and other medical equipment. The most definitive form of evaluation for an acute P. mirabilis infection is a culture. However, positive culture results must be considered in conjunction with a patient's presentation for an accurate diagnosis to be made. This activity describes the presentation and evaluation of Proteus infections and highlights the role of the interprofessional team in the management of infected patients.

Objectives:

• Identify the epidemiology of proteus infections in non-hospitalized versus hospitalized patients.
• Describe the clinical manifestations of Proteus infections.
• Outline the treatment considerations for Proteus infections in hospitalized versus non-hospitalized patients.
• Explain the need for a well-integrated, interprofessional team approach to improve care for patients with Proteus infections.

Introduction

Proteus mirabilis, part of the Enterobacteriaceae family of bacilli, is a gram-negative, facultative anaerobe with an ability to ferment maltose and inability to ferment lactose. P. mirabilis also has swarming motility and the ability to self-elongate and secrete a polysaccharide when in contact with solid surfaces; this allows for attachment and easy motility along surfaces (e.g., medical equipment). The flagella of P. mirabilis are what allow for its motility; not only does this help support colonization, but it also has been associated with its ability to form biofilms and is suggested to contribute to resistance to host defenses and certain antibiotics.[1][2][3][4]

Proteus is found abundantly in soil and water, and although it is part of the normal human intestinal flora (along with Klebsiella species, and Escherichia coli), it has been known to cause serious infections in humans.

Etiology

Ninety percent of Proteus infections occur as a result of P. mirabilis, and these are considered community-acquired infections. [4][5][6]

Though not a common cause of nosocomial infections, Proteus species have also been shown to cause infection from the colonized skin and oral mucosa of patients and personnel working in a hospital or long-term care facility.

Patients who acquire an infection in the hospital, have a history of recurrent infections, structural abnormalities of the urinary tract, or urethral instrumentation have a greater risk of acquiring an infection by Proteus (in addition to other organisms such as Klebsiella, Enterobacter, Pseudomonas, Staphylococci, and Enterococci).

Urinary tract infections (UTIs) occur as a result of bacterial migration along the mucosal sheath of the catheter or up the catheter lumen from contaminated urine.[7][8]

Epidemiology

The most common clinical manifestations of Proteus infection are urinary tract infections (UTIs). In general, UTIs are more common in individuals aged 20 to 50 years and most common in women of this age group. In otherwise healthy women, Proteus accounts for 1% to 2% of all UTIs (E. coli being the most common), while in hospital-acquired UTIs, Proteus accounts for 5%. Complicated UTIs (i.e., secondary to catheterization) have an even higher association with Proteus infection at 20% to 45%.

Risk factors for UTIs include sexual activity in both men and women, unprotected anal intercourse in men, an uncircumcised penis, or immunodeficiency (e.g., CD4 count less than 200/uL).

Other factors that may increase the risk of infection by P. mirabilis include female sex, longer duration of catheterization, improper catheter cleaning or care, underlying illness, and lack of availability of systemic antibiotics.

In the United States, gram-negative bacteremia occurs as a result of genitourinary tract infections in 35% of patients.

Pathophysiology

The interaction between P. mirabilis and the host defense (immune) system determines the resultant infection. Proteus species have an extracytoplasmic outer membrane, like other gram-negative bacteria, which contains lipoproteins, polysaccharides, lipopolysaccharides, and a lipid bilayer. Different components of this membrane interact with the host and host defense mechanisms to determine the organism’s virulence. Additionally, the size of the inoculum has a positive correlation with the level of infection.

Attachment of P. mirabilis to host tissue depends on the activity of its fimbriae (or pili), which are tiny projections on the bacterium surface.  The tips of these fimbriae also contain certain compounds and polysaccharides that allow for attachment to specific sites in the host organism (e.g., endothelium of the urinary tract) or other inanimate surfaces (e.g., medical devices).

Once Proteus species attach to the target site, a cascade of events is initiated in the host cell, including interleukin (IL) 6 and IL-8 secretion in addition to apoptosis and epithelial cell desquamation. Proteus species also produce urease, which has been shown to be associated with an increased risk of pyelonephritis and upper UTIs. Proteus species also hydrolyze urea to ammonia, thereby alkalinizing the urine. Through the production of urease and ammonia, Proteus can produce an environment where it can survive. Additionally, alkaline urine will decrease the solubility of both organic and inorganic compounds, encouraging precipitation and struvite (e.g., magnesium ammonium phosphate and calcium carbonate-apatite) stone formation.

Like other gram-negative bacteria, Proteus species release endotoxin (part of the gram-negative bacterial cell wall) when invading the bloodstream; thereby triggering additional host inflammatory responses which can ultimately result in sepsis or systemic inflammatory response syndrome (SIRS), a severe condition with a 20% to 50% associated incidence of mortality.

History and Physical

Individuals with a Proteus infection may present with urethritis, cystitis, prostatitis, or pyelonephritis. A history of frequent renal stones may be indicative of an underlying chronic Proteus infection.

Urethritis typically presents with dysuria, pyuria (with or without urethral discharge), and increased urinary frequency. Symptoms are often mild and frequently ignored by patients.

Cystitis, on the other hand, tends to present acutely with dysuria, increased frequency, and urgency of urination, suprapubic or back pain, small volume urine, dark urine, or hematuria. Patients also may present with a fever which may be indicative of a more severe condition, such as pyelonephritis, bacteremia, or impending sepsis.

Prostatitis occurs more acutely in men than cystitis, with the same set of symptoms, though may also be accompanied by fever and chills. Prostatitis tends to be more common with increased age. If there is an associated obstruction, patients also may complain of perianal pain. A diffusely swollen and tender prostate may be noted on palpation during a physical examination.

Pyelonephritis occurs as a complication of either of the conditions mentioned above, and the patient may, therefore, complain of symptoms of urethritis or cystitis. Additional symptoms that are more definitive of pyelonephritis include flank pain, costovertebral angle tenderness, nausea and vomiting, fever, hematuria, and occasionally an enlarged kidney felt on palpation.

Evaluation

The most definitive form of evaluation for an acute P. mirabilis infection is a culture. Proteus species are gram-negative, rod-shaped, and facultatively anaerobic. The majority of strains are lactose negative with characteristic swarming motility that will become evident on agar plates. One must always correlate positive culture results with the clinical presentation of the patient to form an accurate diagnosis.

Additional evaluations include urine sample analysis to evaluate for pyuria and leukocyte esterase. Pyuria is generally present in the case of bacterial urinary tract infection, such that lack of pyuria may indicate an alternate cause of symptoms. Leukocyte esterase dipstick provides a good alternative to microscopy but is a less sensitive test than microscopic examination. Gram staining of urine may help reveal microscopic bacteriuria which would confirm infection, although the absence of bacteriuria does not exclude it. 

A patient with a history of chronically alkaline urine in combination with a positive Proteus culture should be evaluated for renal stones (struvite stones).

If resolution is not seen with antibiotic therapy alone, an ultrasound of the kidneys or a CT abdomen may be warranted to rule out renal stones or a perinephric abscess.

Treatment / Management

Empirical treatment for an uncomplicated UTI caused by P. mirabilis (much like other uncomplicated UTIs) involves outpatient treatment with either a 3-day course of trimethoprim/sulfamethoxazole (TMP/SMZ) or an oral fluoroquinolone (e.g., ciprofloxacin).[9][10][11]

Acute, uncomplicated pyelonephritis can be treated on an outpatient basis with fluoroquinolones, although a regimen of 7 to 14 days is recommended. An alternative to this treatment is a one-time dose of ceftriaxone or gentamycin followed by either TMP/SMZ, an oral fluoroquinolone, or cephalosporin for 7 to 14 days.

If a patient has a more severe condition or is in an inpatient setting, they may begin antibiotic therapy via intravenous administration of either ceftriaxone, gentamycin, fluoroquinolone, gentamycin plus ampicillin, or aztreonam until fever resolves. At this point, they may switch to oral therapy with either cephalosporin, an oral fluoroquinolone, or TMP/SMZ for up to 14 additional days.

If a patient presents with a complicated UTI (e.g., a man or woman with a history of an underlying condition that may increase the risk of failure of therapy), they may also be treated in an outpatient setting with oral antibiotics for 10 to 21 days as long as they receive adequate follow-up.

Proteus infection can be avoided with proper sanitation and hygiene, such as adequate sterilization of medical equipment and surfaces.  Additionally, catheterization should be reserved for patients for whom there is no other option.

Differential Diagnosis

Other Gram-negative bacteria, such as E. coli or Klebsiella species, may cause similar clinical presentations with UTI and/or bacteremia. Bacterial culture is essential to identify the causative organism of infection and target therapy appropriately. 

Prognosis

The vast majority of proteus infections are associated with the urinary tract. Most of the infections are sensitive to the currently available antibiotics and the outcomes are good in immunocompetent patients.

Complications

Symptoms generally resolve without complications in immunocompetent patients. Immunocompromised patients can be at higher risk for sepsis or prolonged infections. 

Deterrence and Patient Education

Decreasing risk factors such as prolonged catheterization can decrease the risk of infection. 

Enhancing Healthcare Team Outcomes

Proteus infections are best managed by an interprofessional team that includes physicians, nurses, and pharmacists. Infectious disease specialists may also be helpful, particularly in cases of resistant infections, device-associated infections, or immunocompromised patients.