Proteus Infections

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Background

Proteus species are part of the Enterobacteriaceae family of gram-negative bacilli. 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.

Proteus mirabilis causes 90% of Proteus infections and can be considered a community-acquired infection. Proteus vulgaris and Proteus penneri are easily 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).

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.

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.

Physical

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

Causes

Laboratory Studies

Imaging Studies

Medical Care

Recommended empirical treatment includes the following:

Surgical Care

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] P mirabilis is likely to be sensitive to ampicillin; broad-spectrum penicillins (eg, ticarcillin, piperacillin); first-, second-, and third-generation cephalosporins; imipenem; and aztreonam.

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.[3, 4] 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

Deterrence/Prevention

Complications

Prognosis

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Gus Gonzalez, MD, Medical Oncologist, The Center for Cancer and Blood Disorders

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

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

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: Medscape Salary Employment

Aaron Glatt, MD, Chief Administrative Officer, Executive Vice President, Mercy Medical Center, Catholic Health Services of Long Island

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

References

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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.