Excerpt from Enterobacter Infections

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Background

Enterobacter species, particularly Enterobacter cloacae and Enterobacter aerogenes, are important nosocomial pathogens responsible for various infections, including bacteremia, lower respiratory tract infections, skin and soft tissue infections, urinary tract infections (UTIs), endocarditis, intra-abdominal infections, septic arthritis, osteomyelitis, and ophthalmic infections.

Risk factors for nosocomial Enterobacter species infections include hospitalization of greater than 2 weeks, invasive procedures in the past 72 hours, treatment with antibiotics in the past 30 days, and the presence of a central venous catheter. Specific risk factors for infection with nosocomial multidrug-resistant strains of Enterobacter species include the recent use of broad-spectrum cephalosporins or aminoglycosides and ICU care.

These "ICU bugs" cause significant morbidity and mortality, and infection management is complicated by multiple antibiotic resistance. Enterobacter species possess inducible beta-lactamases, which are undetectable in vitro but are also responsible for resistance during treatment. Physicians treating patients infected with these bacteria are advised to avoid certain antibiotics, particularly third-generation cephalosporins, because resistant mutants can quickly appear. The crucial first step is appropriate identification of the bacteria. Antibiograms must be interpreted with respect to the different resistance mechanisms and their respective frequency, as is reported for bacteria belonging to this genus, even if the resistance mechanisms have not been detected by routine in vitro antibiotic susceptibility testing.

Pathophysiology

Enterobacter species rarely cause disease in a healthy individual. This opportunistic pathogen, similar to other members of the Enterobacteriaceae family, possesses an endotoxin known to play a major role in the pathophysiology of sepsis and its complications.

Although community-acquired infections are occasionally observed, nosocomial infections are, by far, the most frequent. Patients most susceptible to acquiring Enterobacter infections are those who stay in the hospital, especially the ICU, for prolonged periods. Other major risk factors include the prior use of antimicrobial agents, concomitant malignancy (especially hemopoietic and solid organ malignancies) hepatobiliary disease, ulcers of the upper gastrointestinal tract, use of foreign devices such as intravenous catheters, and serious underlying conditions such as burns, mechanical ventilation, and immunosuppression.

The source of infection may be endogenous via colonization of the skin, gastrointestinal tract, or urinary tract or exogenous resulting from the ubiquitous nature of these bacteria. Multiple reports have incriminated the hands of personnel, endoscopes, blood products, devices for monitoring intra-arterial pressure, and stethoscopes as sources of infection. Outbreaks have been traced to various common sources: total parenteral nutrition solutions, isotonic saline solutions, albumin, digital thermometers, and dialysis equipment.

Enterobacter species contain a subpopulation of organisms that produce a beta-lactamase at low-levels. Once exposed to broad-spectrum cephalosporins, the subpopulation of beta-lactamase–producing organisms predominate. Thus, an infection that appears sensitive to cephalosporins at the time of diagnosis may quickly develop into a resistant infection during therapy. Imipenem and cefepime have a more stable beta-lactam ring against the lactamase produced by resistant strains of Enterobacter.

Frequency

United States

National surveillance programs continually demonstrate that Enterobacter species remain a significant source of morbidity and mortality in the hospitalized patient.

In the Surveillance and Control of Pathogens of Epidemiological Importance [SCOPE] project, 24,179 nosocomial bloodstream infections from 1995-2002 were analyzed. Enterobacter species were the second most common gram-negative organism behind Pseudomonas aeruginosa; however, both bacteria were reported to each represent 4.7% of bloodstream infections in the ICU settings. Enterobacter species represent 3.1% of bloodstream infections in non-ICU wards.

Previous reports from the National Nosocomial Infections Surveillance System (NNIS) demonstrated that Enterobacter species caused 11.2% of pneumonia cases in all types of ICUs and ranked third after Staphylococcus aureus (18.1%) and P aeruginosa (17%). The corresponding rates for patients in pediatric ICUs were 9.8% for pneumonia, 6.8% for blood stream infections, and 9.5% for UTIs.

Enterobacter were also among the most frequent pathogens for surgical site infections, as reported in the NNIS report from October 1986 to April 1997. The isolation rate was 9.5% (with enterococci, coagulase-negative staphylococci, S aureus, and P aeruginosa rates being 15.3%, 12.6%, 11.2%, and 10.3%, respectively).

Data on antibiotic resistance are available from the Intensive Care Antimicrobial Resistance Epidemiology (ICARE) surveillance report. The rates of Enterobacter resistance to third-generation cephalosporins were 25.3% in ICUs, 22.3% among non-ICU inpatients, 10.1% among ambulatory patients, and as high as 36.2% in pediatric ICUs.

International

Enterobacter species have a global presence in both adult and neonatal ICUs. Surveillance data and outbreak case reports from North and South America, Europe, and Asia indicate that these bacteria represent an important opportunistic pathogen among debilitated patients in ICUs.

The prevalence of resistance to beta-lactam antibiotics, aminoglycosides, trimethoprim-sulfamethoxazole (TMP-SMZ), and quinolones seems to be higher in different European countries and Israel than in the United States and Canada.

Mortality/Morbidity

The mortality and morbidity resulting from this mostly opportunistic pathogen are considerable.

• These pathogens can cause disease in virtually any body compartment. They are responsible for frequent and severe nosocomial infections that require prolonged hospitalization, multiple and varied imaging studies and lab tests, a variety of different surgical and nonsurgical procedures, powerful and expensive antimicrobial agents, and, most importantly, when not directly causing death, these pathogens cause considerable suffering among numerous patients, most of whom already are afflicted with chronic diseases.
• For bacteremia, the single most important factor in determining mortality appears to be the severity of the underlying disease. Higher 30-day mortality rates were noted in patients presenting with septic shock and increasing Acute Physiology and Chronic Health Evaluation II scores. Other factors implicated, independently or by association, in the outcome of Enterobacter bacteremia include thrombocytopenia, hemorrhage, a concurrent pulmonary focus of infection, renal insufficiency, admission in an ICU, prolonged hospitalization , prior surgery, intravascular and/or urinary catheters, immunosuppressive therapy, neutropenia, antibiotic resistance, and inappropriate antimicrobial therapy.
• Crude mortality rates are 15-87%, but most reported rates are from 20-46%. Attributable mortality rates are reported to vary from 6-40%.
• • E cloacae infection has the highest mortality rate of all Enterobacter infections.
  • Thirty-day mortality rates for bacteremia with cephalosporin-resistant Enterobacter species is significantly higher than infections with susceptible infections (33.7% vs 18.6%.)
  • Mortality rates for pneumonia resulting from Enterobacter infection are higher than those resulting from many other gram-negative bacilli. These rates are from 14-71%. As with bacteremia, the severity of the underlying disease is the major factor that predicts outcome.
  • Other factors that indicate an unfavorable outcome are the extent of the disease as seen on the chest radiographs, corticosteroid therapy, isolation of multiple pathogens from lower respiratory secretions, and, possibly, treatment with a single antibiotic.
  • A review of 17 cases of endocarditis resulting from Enterobacter infection reported an overall mortality rate of 44.4%.

Race

• No racial predilection is known or presumed likely.

Sex

• For Enterobacter bacteremia, reports indicate a male-to-female ratio of 1.3-2.5:1. This male predominance is also reported in the pediatric population.

Age

• Enterobacter infections are observed most frequently in neonates and in elderly individuals, reflecting the increased prevalence of severe underlying diseases at these age extremes. In the pediatric ICU setting, age less than 2.5 years old is a risk factor for colonization.
• Enterobacter sakazakii has been reported as a cause of sepsis and meningitis, complicated by ventriculitis, brain abscess, cerebral infarction, and cyst formation. This clinical pattern appears to be specific to this particular bacterium when it infects neonates and infants.

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