Proteus Infections

Back

Background

Proteus species are part of the Enterobacteriaceae family of gram-negative bacilli. The first isolates were reported and characterized by Hauser in the late 19th century. The genus is currently composed of Proteus mirabilis, Proteus vulgaris, Proteus penneri, Proteus hauseri, Proteus terrae, and Proteus cibarius.P mirabilis and P vulgaris account for most clinical Proteus isolates. Proteus organisms are implicated as serious causes of infections in humans, along with Escherichia, Klebsiella, Enterobacter, and Serratia species.

Proteus species are most commonly found in the human intestinal tract as part of normal human intestinal flora, along with Escherichia coli and Klebsiella species, of which E coli is the predominant resident. Proteus is also found in multiple environmental habitats, including long-term care facilities and hospitals. In hospital settings, it is not unusual for gram-negative bacilli to colonize both the skin and oral mucosa of both patients and hospital personnel. Infection primarily occurs from these reservoirs. However, Proteus species are not the most common cause of nosocomial infections.

P mirabilis causes 90% of Proteus infections and can be considered a community-acquired infection. P vulgaris and P penneri may be isolated from individuals in long-term care facilities and hospitals and from patients with underlying diseases or compromised immune systems.

Patients with recurrent infections, those with structural abnormalities of the urinary tract, those who have had urethral instrumentation, and those whose infections were acquired in the hospital have an increased frequency of infection caused by Proteus and other organisms (eg, Klebsiella, Enterobacter, Pseudomonas, enterococci, staphylococci).

Pathophysiology

Proteus species possess an extracytoplasmic outer membrane, a feature shared with other gram-negative bacteria. In addition, the outer membrane contains a lipid bilayer, lipoproteins, polysaccharides, and lipopolysaccharides.

Infection depends on the interaction between the infecting organism and the host defense mechanisms. Various components of the membrane interplay with the host to determine virulence. Inoculum size is important and has a positive correlation with the risk of infection.

Certain virulence factors have been identified in bacteria. The first step in the infectious process is adherence of the microbe to host tissue. Fimbriae facilitate adherence and thus enhance the capacity of the organism to produce disease. E coli, P mirabilis, and other gram-negative bacteria contain fimbriae (ie, pili), which are tiny projections on the surface of the bacterium. Specific chemicals located on the tips of pili enable organisms to attach to selected host tissue sites (eg, urinary tract endothelium). The presence of these fimbriae has been demonstrated to be important for the attachment of P mirabilis to host tissue.

The attachment of Proteus species to uroepithelial cells initiates several events in the mucosal endothelial cells, including secretion of interleukin 6 and interleukin 8. Proteus organisms also induce apoptosis and epithelial cell desquamation. Bacterial production of urease has also been shown to increase the risk of pyelonephritis in experimental animals. Urease production, together with the presence of bacterial motility and fimbriae, may favor the production of upper urinary tract infections (UTIs) by organisms such as Proteus.

Enterobacteriaceae (of which Proteus is a member) and Pseudomonas species are the microorganisms most commonly responsible for gram-negative bacteremia. When these organisms invade the bloodstream, endotoxin, a component of gram-negative bacterial cell walls, apparently triggers a cascade of host inflammatory responses and leads to major detrimental effects. Because Proteus and Pseudomonas organisms are gram-negative bacilli, they can cause gram-negative endotoxin-induced sepsis, resulting in systemic inflammatory response syndrome (SIRS), which carries a mortality rate of 20%-50%.

Although other organisms can trigger a similar response, it is useful to consider gram-negative bacteremia as a distinct entity because of its characteristic epidemiology, pathogenesis, pathophysiology, and treatment. The presence of the sepsis syndrome associated with a UTI should raise the possibility of urinary tract obstruction. This is especially true of patients who reside in long-term care facilities, who have long-term indwelling urethral catheters, or who have a known history of urethral anatomic abnormalities.

The ability of Proteus organisms to produce urease and to alkalinize the urine by hydrolyzing urea to ammonia makes it effective in producing an environment in which it can survive. This leads to precipitation of organic and inorganic compounds, which leads to struvite stone formation. Struvite stones are composed of a combination of magnesium ammonium phosphate (struvite) and calcium carbonate-apatite.

Struvite stone formation can be sustained only when ammonia production is increased and the urine pH is elevated to decrease the solubility of phosphate. Both of these requirements can occur only when urine is infected with a urease-producing organism such as Proteus. Urease metabolizes urea into ammonia and carbon dioxide: Urea → 2NH3 + CO2. The ammonia/ammonium buffer pair has a pK of 9.0, resulting in the combination of highly alkaline urine rich in ammonia.

Symptoms attributable to struvite stones are uncommon. More often, women present with UTI, flank pain, or hematuria and are found to have a persistently alkaline urine pH (>7.0).

The acquisition of a particular phenotype known as "swarm cell differentiation" facilitates the ascent of P mirabilis into the urinary tract. The swarming behavior of Proteus species results in a characteristic bullseye pattern on a plate culture. When Proteus species swarm, the production of secreted proteins, including virulence factors such as the protease ZapA, dramatically increases,. This swarming motility is regulated through a complex network acting on the flagellar transcription regulator flhDC. The name Proteus follows from the character in Homer's Odyssey who is capable of changing form.

Epidemiology

Frequency

United States

The genitourinary tract is the site of disease responsible for gram-negative bacteremia in approximately 35% of patients. In previously healthy outpatients, E coli is by far the most often implicated cause of UTIs. In contrast, individuals with multiple prior episodes of UTI, multiple antibiotic treatments, urinary tract obstruction, or infection developing after instrumentation frequently become infected with Proteus bacteria or other bacteria such as Enterobacter, Klebsiella, Serratia, and Acinetobacter.

Bacteriuria occurs in 10%-15% of hospitalized patients with indwelling catheters. The risk of infection is 3%-5% per day of catheterization.

Mortality/Morbidity

Among long-term care residents, UTIs are the second most common infection responsible for hospital admission, second only to pneumonia. UTIs can result in sepsis if not recognized and treated rapidly. Failure to treat or a delay in treatment can result in SIRS, which carries a mortality rate of 20%-50%.

Sex

Other factors that increase infection rates include female sex, duration of catheterization, underlying illness, faulty catheter care, and lack of systemic antibiotic therapy. Infection occurs either by migration of bacteria up the catheter along the mucosal sheath or by migration up the catheter lumen from infected urine.

UTIs are the most common clinical manifestation of Proteus infections. Proteus infection accounts for 1%-2% of UTIs in healthy women and 5% of hospital-acquired UTIs. Complicated UTIs (ie, those associated with catheterization) have a prevalence of 20%-45%.

UTIs are more common in males then females in the neonatal population. This is a result of congenital abnormalities seen more often in males.

After age 50 years, the ratio between men and women begins to decline because of the increasing incidence of prostate disease. UTIs in men younger than 50 years are usually caused by urologic abnormalities.

Age

UTIs are more common in persons aged 20-50 years.

History

Approximately 95% of UTIs occur when bacteria ascend through the urethra and the bladder.

Complicated UTIs occur with instrumentation (including Foley catheters), obstruction, calculi, or neurogenic bladder. These carry a higher risk for complications such as hospitalization and sepsis.

Sexually active women are at greater risk for UTIs. The same is true for men, although to a lesser degree.

Other predisposing factors for UTIs are men who have unprotected anal intercourse, an uncircumcised penis, unprotected vaginal intercourse, and/or CD4 count less than 200/µL.

Although infrequent, chronic prostatitis should be considered in males with a history of recurrent UTIs. Obstructive symptoms are transient but may progress to infect the bladder because of poor bladder emptying.

Frequent and unexplained incidents of renal calculi may be indicative of a chronic Proteus infection. Multiple magnesium ammonium phosphate crystals are present in the urine sediment along with radio dense renal calculus. (This calculus is less radio dense than calcium oxalate.) This results in formation and precipitation of struvite crystals, a predominant component of urinary calculi and encrustations on urinary catheters.

Proteus are common among the gram-negative causes of bacteremia, with most cases secondary to UTI and often associated with urinary catheters. Community-acquired Proteus UTI in the presence of hydronephrosis or urolithiasis increases the risk of bacteremia. Proteus can persist in the urinary tract despite antibiotics and catheter exchange, potentially because of immune evasion and the protective reservoir that urinary stones may provide.

Physical

Patients may present with urethritis, cystitis, prostatitis, or pyelonephritis. Chronic, recurring stones may be an indication of chronic infection.

Urethritis

Symptoms of urethritis are usually mild and may be dismissed by the patient.

Women present with dysuria, pyuria, and increased frequency of urination.

Presenting symptoms in males are usually mild and may include urethral discharge.

Cystitis

Signs and symptoms of cystitis tend to be more prominent compared to those of urethritis.

In both men and women, symptoms are of sudden onset.

They include dysuria, increased frequency, urgency, suprapubic pain, back pain, small volumes, concentrated appearance, and hematuria. If the patient is febrile, this could be a sign of bacteremia and impending sepsis. These symptoms may not be present if the patient has an indwelling catheter. Physical examination findings may include abdominal or pelvic pain and/or costovertebral angle tenderness.

Prostatitis

Prostatitis is obviously limited to men and occurs more acutely than cystitis. This becomes more common as men age.

In addition to symptoms of cystitis, patients with prostatitis may present with fever and chills.

Perianal pain and various symptoms of urinary tract obstruction may be present. The prostate may be tender and diffusely swollen.

Pyelonephritis

Pyelonephritis can be considered a progression of disease, and symptoms are therefore more profound. Sepsis can develop quickly, especially in elderly patients or those with a compromised immune system.

Symptoms of urethritis and cystitis may or may not be present.

Defining symptoms of pyelonephritis include flank pain, nausea and vomiting, costovertebral angle tenderness, fever, and, rarely, a palpable and tender kidney. Hematuria and pyuria are frequently encountered.

Causes

Hospital-acquired infections are usually caused by interruption of the closed sterile system by hospital personnel.

Proteus species also cause sepsis neonatorum and bacteremia with fever and neutropenia.

Proteus species are also involved in synergistic nonclostridial anaerobic myonecrosis, which may involve subcutaneous tissue, fascia, and muscle. This condition is caused by combinations of other aerobic gram-negative bacilli (E coli or Klebsiella or Enterobacter species) and anaerobes. Surgical evaluation and intervention is critical to successful treatment.

Laboratory Studies

Proteus organisms are easily recovered through routine laboratory cultures. Most strains are lactose-negative and demonstrate characteristic swarming motility on agar plates. Any positive culture result from an otherwise sterile area should be considered an acute infection if clinical signs and symptoms are present.



View Image

After 24 hours, this inoculated MacConkey agar culture plate cultivated colonial growth of gram-negative, rod-shaped, and facultatively anaerobic Prot....

UTIs in symptomatic patients have traditionally been defined by recovering bacteria in large numbers (ie, >100,000 colony-forming units [CFUs]/mL) on examination. Bacterial counts of less than 100,000 CFUs/mL may indicate infection in urine samples, especially if obtained directly from the ureters or renal pelvis, whereas specimens from suprapubic catheters usually have bacterial counts greater than 100,000 CFUs/mL. However, even small numbers of organisms may be of true clinical significance in symptomatic patients (eg, women with the urethral syndrome).

Microscopic bacteriuria is best evaluated through uncentrifuged Gram staining of the urine. Microscopic bacteriuria is found in 90% of cases when bacterial counts exceed 100,000 CFUs/mL. Detection by microscopy confirms infection, but absence does not exclude infection. Pyuria is demonstrated in nearly all acute bacterial infections, but its absence calls the diagnosis into question. The leukocyte esterase dipstick test is a useful alternative to microscopic examination, but this method is less sensitive than microscopy.

Persistently alkaline urine with a positive Proteus culture finding should prompt an examination for renal calculi.

Although cultures are the most definitive way of confirming an acute Proteus infection, they are often prohibitively expensive and take time for complete identification. Cultures are most effective when patients do not respond to empiric therapy or when they have recurrent symptoms.

Imaging Studies

Ultrasonography of the kidneys or a CT scan should be considered as part of a workup for Proteus infection of the urinary tract that does not resolve quickly with antimicrobial therapy. Calices and/or perinephric abscesses should be excluded. Given the increased severity of Proteus UTIs and the propensity of the organism to cause bacteremia in community-acquired infections and in patients with hydronephrosis or urolithiasis, radiographic studies such as renal ultrasonography or CT scanning should be considered in patients with severe UTIs, especially when complicated by bacteremia.

Medical Care

Cultures with susceptibility data are recommended, when available, to guide antimicrobial therapy. Most Proteus strains are susceptible to commonly used antibiotics, except nitrofurantoin and tetracycline. Like other members of Enterobacteriaceae, multidrug-resistant (MDR) strains of Proteus exist and are increasing in frequency; strains of P vulgaris are generally more resistant.

Recommended empirical treatment includes the following:

Surgical Care

If struvite renal calculus is associated with Proteus infection, it must be removed to avert severe clinical outcomes and to avoid persistent sources that can lead to recurrent infection.

Most nonurologic infections result in abscesses. Radical surgical debridement is the cornerstone of successful therapy. Amputation may be necessary if skin or muscle necrosis of an extremity is the presenting infection, but tissue recovery is often better than expected. Broad-spectrum antimicrobial therapy is started empirically and is modified by the results of smears and cultures. Mortality and morbidity rates are high, even with adequate treatment.

Consultations

The discovery of stones requires an evaluation by a physician knowledgeable in the short- and long-term management of stones, typically a urologist or nephrologist.

Medication Summary

Serious and occasionally fatal hypersensitivity (ie, anaphylactoid) reactions have occurred in patients receiving antibiotics. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. Cross-sensitivity between penicillins and cephalosporins has occurred. If a reaction occurs, discontinue the implicated drug unless the condition is life threatening and amenable only to therapy with that antibiotic. Serious anaphylactoid reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be used as indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents and has ranged in severity from mild to life threatening. This diagnosis must therefore be considered in patients who present with diarrhea subsequent to the administration of antibacterial agents. Antibiotic treatment alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic colitis. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consider treatment with fluids and electrolytes, protein supplementation, and an antibacterial drug effective against C difficile.

Antibiotic therapy requires constant observation for signs of overgrowth of nonsusceptible organisms, including fungi. Overgrowth more usually occurs in the setting of chronic UTIs or in patients with indwelling catheters than in uncomplicated UTIs. If superinfection occurs (usually involving Aerobacter, Pseudomonas, or Candida organisms), discontinue the offending drug and/or institute appropriate therapy. As with any potent agent, it is advisable to periodically check for organ system dysfunction during prolonged therapy, to include the renal, hepatic, and hematopoietic systems. This measure is particularly important in premature infants, neonates, and other infants.

P mirabilis remains susceptible to nearly all antimicrobials except tetracycline. Resistance does not appear to be a significant clinical factor, but 10%-20% of strains can acquire resistance to ampicillin and first-generation cephalosporins. Acquisition of resistance to extended-spectrum alpha-lactamases remains uncommon, but concern exists regarding the emergence of extended-spectrum beta-lactamase–producing organisms, most notably E coli.[1, 2, 3, 4] P mirabilis is likely to be sensitive to ampicillin; broad-spectrum penicillins (eg, ticarcillin, piperacillin); first-, second-, and third-generation cephalosporins; imipenem; and aztreonam.[5]

P vulgaris and P penneri are resistant to ampicillin and first-generation cephalosporins. Activation of an inducible chromosomal beta-lactamase (not found in P mirabilis) occurs in up to 30% of these strains. Imipenem, fourth-generation cephalosporins, aminoglycosides, TMP/SMZ, and quinolones have excellent activity (90%-100%). Consult the local infectious disease sensitivity surveillance for appropriate empiric therapy.

In addition, the use of chlorhexidine and triclosan in closed urinary catheterization systems and drug-impregnated catheters reduce the incidence of Proteus UTI in patients with long-term indwelling urinary catheters.[6, 7] While the use of these types of catheters for Proteus UTIs is helpful in containing the migration of Proteus in experimental models, this practice is not widespread, as other, more common, uropathogens are resistant to the drugs used in these systems.

A vaccine derived from purified mannose-resistant Proteus -like (MR/P) fimbriae proteins has been proven to prevent infection in mouse models and is under clinical research, but it is not available commercially. Vaccine description is beyond the scope of this article.

Ceftriaxone (Rocephin)

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin-binding proteins. Highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of dose excreted unchanged in urine, and remainder secreted in bile and ultimately in feces as microbiologically inactive compounds. At 1-3 h after 1-g IV dose, average concentrations determined were 581 mcg/mL in gallbladder bile, 788 mcg/mL in common duct bile, 898 mcg/mL in cystic duct bile, 78.2 mcg/g in gallbladder wall, and 62.1 mcg/mL in concurrent plasma. In healthy adult subjects, over 0.15-3 g dose, range of elimination half-life is 5.8-8.7 h. Apparent volume of distribution is 5.78-13.5 L, plasma clearance is 0.58-1.45 L/h, and renal clearance is0.32-0.73.

L/h. Reversibly bound to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.

Trimethoprim and sulfamethoxazole, TMP/SMZ (Septra, Septra DS, Bactrim)

Clinical Context:  Blocks 2 consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. SMZ inhibits bacterial synthesis of dihydrofolic acid by competing with PABA. TMP blocks production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting required enzyme, dihydrofolate reductase. In vitro studies indicate that bacterial resistance develops more slowly with TMP/SMZ combination than with either component alone. In vitro serial dilution tests indicate that the spectrum of antibacterial activity includes common urinary tract pathogens with exception of P aeruginosa. The following organisms are usually susceptible: E coli, Klebsiella and Enterobacter species, Morganella morganii,P mirabilis, and indole-positive Proteus species, including P vulgaris.

Additional information for PO use:

PO products available: Tab (80 mg TMP/400 mg SMZ); double-strength (DS) tab (160 mg TMP/800 mg SMZ); susp (TMP 40 mg/5mL and SMZ 200 mg/5 mL)

Levofloxacin (Levaquin)

Clinical Context:  Mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination. Has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides, and beta-lactam antibiotics, including penicillins. Fluoroquinolones may therefore be active against bacteria resistant to these antimicrobials.

Ampicillin (Omnipen, Polycillin)

Clinical Context:  Like benzyl penicillin, is bactericidal against sensitive organisms during active multiplication. Inhibits biosynthesis of cell wall mucopeptide. Not effective against penicillin-producing bacteria, particularly resistant staphylococci. All strains of Pseudomonas and most strains of Klebsiella and Aerobacter organisms are resistant.

Aztreonam (Azactam)

Clinical Context:  Exhibits potent and specific activity in vitro against a wide spectrum of gram-negative aerobic pathogens, including P aeruginosa. Active over a pH range of 6-8 in vitro, as well as in presence of human serum and under anaerobic conditions. Combined with aminoglycosides, demonstrates synergistic activity in vitro against most strains of P aeruginosa. Duration of therapy depends on severity of infection and continues for at least 48 h after patient is asymptomatic or evidence of bacterial eradication is obtained. Doses smaller than indicated should not be used. Transient or persistent renal insufficiency may prolong serum levels. After an initial loading dose of 1 or 2 g, reduce dose by one half for estimated CrCl of 10-30 mL/min/1.73/m2. When only serum creatinine concentration is available, the following formula (based on sex, weight, and age) can approximate CrCl. Serum creatinine should represent a steady state of renal function.

Males: CrCl = [(weight in kg)(140 - age)] ÷(72 X serum creatinine in mg/dL)

Females: 0.85 X above value.

In patients with severe renal failure (CrCl < 10 mL/min/1.73/m2) and those supported by hemodialysis, usual dose of 500 mg, 1 g, or 2 g is initially administered. Maintenance dose is one fourth of usual initial dose given at usual fixed interval of 6, 8, or 12 h.For serious or life-threatening infections, supplement maintenance doses with one eighth of initial dose after each hemodialysis session. Elderly persons may have diminished renal function. Renal status is a major determinant of dosage in these patients. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by kidneys, obtain estimates of CrCl, and make appropriate dosage modifications. Insufficient data are available regarding IM administration to pediatric patients or dosing in pediatric patients with renal impairment. Administered IV only to pediatric patients with normal renal function.

Ticarcillin and Clavulanate (Timentin)

Clinical Context:  Demonstrates substantial in vitro bactericidal activity against gram-positive and gram-negative organisms. Not stable in presence of penicillinase. Exhibits in vitro synergism with aminoglycosides (gentamicin, tobramycin, amikacin) against certain strains of P aeruginosa.

Imipenem and cilastatin (Primaxin)

Clinical Context:  Demonstrates in vitro activity against a wide range of gram-positive and gram-negative organisms. Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, it is useful for the treatment of mixed infections and as presumptive therapy prior to the identification of the causative organisms. Although clinical improvement has been observed in patients with cystic fibrosis, chronic pulmonary disease, and lower respiratory tract infections caused by P aeruginosa, bacterial eradication may not necessarily be achieved.

Potent inhibitor of beta-lactamases from certain gram-negative bacteria that are inherently resistant to most beta-lactam antibiotics (eg, P aeruginosa,Serratia and Enterobacter species). As with some other beta-lactam antibiotics, some strains of P aeruginosa may develop resistance fairly rapidly during treatment. Therefore, perform periodic susceptibility testing when clinically appropriate. Base total daily dosage on type or severity of infection and administer in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function, and body weight. Dosage recommendations reflect quantity of imipenem component administered. Corresponding amount of cilastatin is also present in solution. A product that is only for IM use is available.

Piperacillin and Tazobactam (Zosyn)

Clinical Context:  Exerts bactericidal activity by inhibiting both septum and cell wall synthesis. Active against various gram-positive and gram-negative aerobic and anaerobic bacteria. Inactivated in vitro by staphylococcal beta-lactamase and beta-lactamase produced by gram-negative bacteria. Its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria makes it particularly useful for treatment of mixed infections and presumptive therapy prior to the identification of the causative organisms. Administered IM or IV.

Gentamicin (Garamycin)

Clinical Context:  Bactericidal antibiotic (demonstrated by in vitro tests) that inhibits normal protein synthesis in susceptible microorganisms. Active against a wide variety of pathogenic bacteria, including E coli, Proteus species (indole-positive and indole-negative), Pseudomonas aeruginosa; species of Klebsiella, Enterobacter, and Serratia; Citrobacter species; and Staphylococcus species (including penicillin- and methicillin-resistant strains). The following organisms are usually resistant to aminoglycosides: Streptococcus pneumoniae, most species of streptococci, particularly group D and anaerobic organisms (ie, Bacteroides or Clostridium species). In vitro studies demonstrate that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some group D streptococcal strains.

Combination of gentamicin and penicillin G has a synergistic bactericidal effect against virtually all strains of Streptococcus faecalis and its variants (ie, Streptococcus faecalis var liquefaciens,Streptococcus faecalis var zymogenes), Streptococcus faecium, and Streptococcus durans. An enhanced killing effect against many of these strains occurs in vitro when combined with ampicillin, carbenicillin, nafcillin, or oxacillin. Combined effect of gentamicin and carbenicillin is synergistic for many strains of P aeruginosa. In vitro synergism against other gram-negative organisms occurs when combined with cephalosporins.

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Further Inpatient Care

Repeat blood cultures, if positive, to document clearance.

Remove catheters as soon as possible. Replace only if required and only after patient has completely responded to therapy.

Switch from intravenous to oral therapy as soon as possible once directed based on identification and sensitivities.

Monitor renal function and provide adequate fluid support either via the intravenous or oral route.

Deterrence/Prevention

Avoid procedures that introduce bacteria through the urethra and devices that come into contact with the urethra. Postprocedure antimicrobials are appropriate for high-risk individuals.

Complications

Other presentations of hematogenous spread must also be considered.

The presence of calculi results in obstruction of urinary flow. This increases the risk of perinephric abscesses and is associated with them 20%-60% of the time. While a single species may be recovered through culture, multiple species may also be found. If multiple organisms are cultured, consider a perinephric or renal abscess.

Intraspinal bacterial infections most often occur within the posterior epidural space. Bacteria may gain access to the epidural space through hematogenous spread from distant infections, usually in the skin or pelvic structures, or by contiguous spread from adjacent vertebral osteomyelitis. Penetrating injuries may also implant bacteria in the epidural space. Staphylococcus aureus is the most common causative organism, being isolated in 60%-90% of cases. Proteus species, along with E coli,P aeruginosa,S pneumoniae, and Klebsiella species have been reported.

Meningitis is a more common predisposing condition in neonates and infants. Gram-negative organisms and Proteus and Citrobacter species are the most frequent causative organisms.

Acute infection of the stomach may produce diffuse phlegmonous or suppurative gastritis. This rare condition probably arises from preexisting disease of the stomach, such as damage by ethanol or noxious agents, chronic gastritis, trauma, or upper gastrointestinal surgery. Alpha-hemolytic streptococci are the most common organisms involved, although P vulgaris and other bacteria (eg, E coli, Clostridium perfringens, Bacillus subtilis, staphylococci, pneumococci) have been implicated. Suppurative gastritis is a medical emergency with a high mortality rate and may necessitate surgical resection after appropriate treatment with fluids, electrolytes, and antibiotics.

A spinal epidural abscess may extend over many spinal levels. The epidural mass may consist of pus and granulation tissue in acute cases or of fibrous granulation tissue in chronic cases.

The thoracic spine is the site of the abscess in 50%-80% of patients, followed in frequency by the cervical and lumbar spine. Isolated epidural abscesses resulting from hematogenous spread generally occur dorsal to the thecal sac, whereas contiguous spread of infection from an underlying osteomyelitis collects anterior to the thecal sac.

Prognosis

Treatment of uncomplicated UTIs has a low mortality/morbidity index and can be treated with a short course of empiric antibiotic therapy.

Recurrence rates are directly influenced by eradicating the underlying cause (ie, catheter, anatomical obstruction, renal calculi).

Once the infectious agent spreads beyond the bladder, morbidity and mortality increase significantly. If hematogenous spread occurs, the chance of death can be as high as 30%-45% despite the use of antibiotic therapy and intensive care. Patients with preexisting medical problems, neonates, and elderly individuals are at the greatest risk for complications.

Patient Education

Education concerning catheter care may reduce the frequency of infections.

What are Proteus species?Where are Proteus species most commonly found?What causes most Proteus infections?Which factors increase the risk of Proteus infection?What is the pathophysiology of Proteus infection?Which factors influence virulence of Proteus infection?What is the role of fimbriae in the pathogenesis of Proteus infection?What is the role of urease production in the pathogenesis of Proteus infections?What is the pathogenesis of systemic inflammatory response syndrome (SIRS) in Proteus infections?What is the pathogenesis of struvite stones in Proteus infections?What is the prevalence of Proteus infections in the US?What are the mortality rates and morbidity associated with Proteus infections?How does the prevalence of Proteus infections differ between males and females?In what age groups are Proteus infections most prevalent?What are the risk factors for Proteus UTIs?What condition is suggested by a history of recurrent Proteus UTIs in men?Which history findings suggest chronic Proteus infections?What are the signs and symptoms of Proteus infections?What are the signs and symptoms of Proteus urethritis?What are the signs and symptoms of Proteus cystitis?What are the signs and symptoms of Proteus prostatitis?What are the signs and symptoms of Proteus pyelonephritis?What can cause hospital-acquired Proteus infections?What is synergistic nonclostridial anaerobic myonecrosis?What are the differential diagnoses for Proteus Infections?Which lab tests are performed to diagnose suspected Proteus infections?How are Proteus UTIs diagnosed?How is microscopic bacteriuria evaluated in the workup of Proteus infections?Which finding in the evaluation of Proteus infections should prompt an exam for renal calculi?What is the role of bacterial cultures in the workup of Proteus infections?What is the role of imaging studies in the workup of Proteus infections?What are the treatment options for Proteus infections?What is the indication for surgical treatment of Proteus infections?When are specialist consultations indicated in Proteus infections?What are the possible complications of antibiotic treatment of Proteus infections?What should be monitored during antibiotic therapy for Proteus infections?How prevalent is antibiotic resistance in Proteus infections?What reduces the incidence of Proteus UTI in patients with long-term indwelling urinary catheters?Which vaccine is effective against Proteus infections?Which medications in the drug class Antibiotics are used in the treatment of Proteus Infections?How are inpatient Proteus infections treated?How can Proteus infections be prevented?What are the possible renal complications of Proteus infections result in?How do intraspinal Proteus infections occur?Which group is at risk for Proteus meningitis?What are the GI complications of Proteus infections?How are spinal epidural abscess caused by Proteus infection characterized?What is the prognosis of Proteus infections?Which factors affect recurrence rates in Proteus infections?When does the morbidity and mortality of Proteus infections increase?What education should patients with Proteus infections receive?

Author

Shirin A Mazumder, MD, FIDSA, Associate Professor of Medicine, Director of Infectious Disease Fellowship Program, Division of Infectious Diseases, Department of Internal Medicine, University of Tennessee Health Science Center College of Medicine, University of Tennessee Methodist Physicians

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Aaron Glatt, MD, Chairman, Department of Medicine, Chief, Division of Infectious Diseases, Hospital Epidemiologist, South Nassau Communities Hospital

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Gus Gonzalez, MD, Medical Oncologist, Cox Medical Center Branson and CoxHealth Springfield

Disclosure: Nothing to disclose.

Acknowledgements

Rhett L Jackson, MD Associate Professor and Vice Chair for Education, Department of Medicine, Director, Internal Medicine Residency Program, University of Oklahoma College of Medicine; Assistant Chief, Medicine Service, Oklahoma City Veterans Affairs Hospital

Rhett L Jackson, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Medical Association

Disclosure: Nothing to disclose.

Kelley Struble, DO Fellow, Department of Infectious Diseases, University of Oklahoma College of Medicine

Kelley Struble, DO is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

References

  1. Luzzaro F, Brigante G, D'Andrea MM, Pini B, Giani T, Mantengoli E, et al. Spread of multidrug-resistant Proteus mirabilis isolates producing an AmpC-type beta-lactamase: epidemiology and clinical management. Int J Antimicrob Agents. 2009 Apr. 33(4):328-33. [View Abstract]
  2. Lewis JS 2nd, Herrera M, Wickes B, Patterson JE, Jorgensen JH. First report of the emergence of CTX-M-type extended-spectrum beta-lactamases (ESBLs) as the predominant ESBL isolated in a U.S. health care system. Antimicrob Agents Chemother. 2007 Nov. 51(11):4015-21. [View Abstract]
  3. Wang JT, Chen PC, Chang SC, Shiau YR, Wang HY, Lai JF, et al. Antimicrobial susceptibilities of Proteus mirabilis: a longitudinal nationwide study from the Taiwan surveillance of antimicrobial resistance (TSAR) program. BMC Infect Dis. 2014 Sep 5. 14:486. [View Abstract]
  4. Helmy MM, Wasfi R. Phenotypic and molecular characterization of plasmid mediated AmpC ß-lactamases among Escherichia coli, Klebsiella spp., and Proteus mirabilis isolated from urinary tract infections in Egyptian hospitals. Biomed Res Int. 2014. 2014:171548. [View Abstract]
  5. Tsai HY, Chen YH, Tang HJ, Huang CC, Liao CH, Chu FY, et al. Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum ß-lactamase-producing Proteus mirabilis. Diagn Microbiol Infect Dis. 2014 Jul 26. [View Abstract]
  6. Williams GJ, Stickler DJ. Effect of triclosan on the formation of crystalline biofilms by mixed communities of urinary tract pathogens on urinary catheters. J Med Microbiol. 2008 Sep. 57:1135-40. [View Abstract]
  7. Gaonkar TA, Caraos L, Modak S. Efficacy of a silicone urinary catheter impregnated with chlorhexidine and triclosan against colonization with Proteus mirabilis and other uropathogens. Infect Control Hosp Epidemiol. May 2007. 28:596-8. [View Abstract]
  8. Beck-Sague C, Villarino E, Giuliano D, et al. Infectious diseases and death among nursing home residents: results of surveillance in 13 nursing homes. Infect Control Hosp Epidemiol. 1994 Jul. 15(7):494-6. [View Abstract]
  9. Braunwald E, Fauci AS, Kasper DL. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw Hill, Inc; 2001.
  10. Dembry LM, Andriole VT. Renal and perirenal abscesses. Infect Dis Clin North Am. 1997 Sep. 11(3):663-80. [View Abstract]
  11. Endimiani A, Luzzaro F, Brigante G, et al. Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum beta-lactamases. Antimicrob Agents Chemother. 2005 Jul. 49(7):2598-605. [View Abstract]
  12. Engel JD, Schaeffer AJ. Evaluation of and antimicrobial therapy for recurrent urinary tract infections in women. Urol Clin North Am. 1998 Nov. 25(4):685-701, x. [View Abstract]
  13. Kaye D, Tunkel AR, Fournier GR. Stein, ed. Internal Medicine. 5th ed. St Louis, Mo: Mosby-Year Book; 1998.
  14. Li X, Lockatell CV, Johnson DE, et al. Development of an intranasal vaccine to prevent urinary tract infection by Proteus mirabilis. Infect Immun. 2004 Jan. 72(1):66-75. [View Abstract]
  15. Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med. 1989 Jan 15. 110(2):138-50. [View Abstract]
  16. Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000.
  17. Pewitt EB, Schaeffer AJ. Urinary tract infection in urology, including acute and chronic prostatitis. Infect Dis Clin North Am. 1997 Sep. 11(3):623-46. [View Abstract]
  18. Roberts JA. Management of pyelonephritis and upper urinary tract infections. Urol Clin North Am. 1999 Nov. 26(4):753-63. [View Abstract]
  19. Schwartz BF, Stoller ML. Nonsurgical management of infection-related renal calculi. Urol Clin North Am. 1999 Nov. 26(4):765-78, viii. [View Abstract]
  20. Walsh PC, Schaeffer AJ. Walsh PC, Schaeffer AJ, eds. Campbell's Urology. 7th ed. Philadelphia, Pa: WB Saunders; 1997.
  21. Warren JW. Catheter-associated urinary tract infections. Infect Dis Clin North Am. 1997 Sep. 11(3):609-22. [View Abstract]
  22. Wu YL, Liu KS, Yin XT, Fei RM. GlpC gene is responsible for biofilm formation and defense against phagocytes and imparts tolerance to pH and organic solvents in Proteus vulgaris. Genet Mol Res. 2015 Sep 9. 14 (3):10619-29. [View Abstract]
  23. Pearson M, Rasko DA, Smith SN, Mobley HL. Transcriptome of swarming Proteus mirabilis. Infect Immun. June 2010. 78(6):2834-45. [View Abstract]

After 24 hours, this inoculated MacConkey agar culture plate cultivated colonial growth of gram-negative, rod-shaped, and facultatively anaerobic Proteus vulgaris bacteria. Courtesy of the CDC.

After 24 hours, this inoculated MacConkey agar culture plate cultivated colonial growth of gram-negative, rod-shaped, and facultatively anaerobic Proteus vulgaris bacteria. Courtesy of the CDC.