Practice Essentials
Enterobacter infections can include bacteremia, lower respiratory tract infections, skin and soft tissue infections, urinary tract infections (UTIs), endocarditis, intra-abdominal infections, septic arthritis, osteomyelitis, CNS infections, and ophthalmic infections. [1] Enterobacter infections can necessitate prolonged hospitalization, multiple and varied imaging studies and laboratory tests, various surgical and nonsurgical procedures, and powerful and expensive antimicrobial agents. [2]
Signs and symptoms
Enterobacter infections do not have a clinical presentation that is specific enough to differentiate them from other acute bacterial infections.
Bacteremia
Signs of Enterobacter bacteremia include the following:
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Physical examination and laboratory findings consistent with systemic inflammatory response syndrome (SIRS): Including heart rate that exceeds 90 bpm, a respiratory rate greater than 20, a temperature above 38°C or below 36°C, and a WBC of over 12,000 or under 4000/microliter
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Fever: Occurring in more than 80% of children and adults with Enterobacter bacteremia
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Hypotension and shock: Occurs in as many as one third of cases
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Septic shock: Manifested as disseminated intravascular coagulation, jaundice, acute respiratory distress syndrome, and other complications of organ failure
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Purpura fulminans and hemorrhagic bullae
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Ecthyma gangrenosum
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Cyanosis and mottling: Frequently reported in children with Enterobacter bacteremia [2]
Lower respiratory tract infections
Enterobacter lower respiratory tract infections can manifest identically to those caused by Streptococcus pneumoniae or other organisms. The physical examination findings may include the following:
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Apprehension
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High fever or hypothermia
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Tachycardia
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Hypoxemia
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Tachypnea
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Cyanosis [2]
Patients with pulmonary consolidation may present with crackling sounds, dullness to percussion, tubular breath sounds, and egophony. Pleural effusion may manifest as dullness to percussion and decreased breath sounds.
See Clinical Presentation for more detail.
Diagnosis
Laboratory studies
Studies for the evaluation of Enterobacter infections include the following:
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Complete blood count
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Creatinine level
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Electrolyte evaluation
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Fluid analysis, recommendeded for pleural, articular, pericardial, peritoneal, and cerebrospinal fluids; studies may include cell count and differential, protein, glucose, and, in some cases, pH, lactate dehydrogenase, and amylase
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Urine analysis: Always indicated for urinary tract infections (UTIs)
Factors in the microbiologic diagnosis and assessment of Enterobacter infection include the following:
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The most important test to document Enterobacter infections is culture; when the patient presents with signs of systemic inflammation (eg, fever, tachycardia, tachypnea, elevated or depressed WBC) with or without shock (eg, hypotension, decreased urinary output), blood cultures are mandatory
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Direct Gram staining of the specimen is also useful, because it allows rapid diagnosis of an infection caused by gram-negative bacilli and helps in the selection of antibiotics with known activity against most of these bacteria
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In the laboratory, growth of Enterobacter isolates is expected to be detectable in 24 hours or less; Enterobacter species grow rapidly on selective (ie, MacConkey) and nonselective (ie, sheep blood and chocolate) agars
Imaging studies
Studies used in the investigation and management of Enterobacter infections include the following:
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Chest infections: Serial chest radiography, chest ultrasonography, and computed tomography (CT) scanning
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Intra-abdominal infections: CT scanning and ultrasonography
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Endocarditis and intravascular infections: Echocardiography (preferably transesophageal) and nuclear indium scanning
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UTIs: Renal ultrasonography; occasionally, CT scanning and pyelography
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Central nervous system (CNS) and ophthalmic infections: CT scanning and/or magnetic resonance imaging (MRI)
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Bone and joint infections: Plain radiography, CT scanning and/or MRI studies, nuclear medicine studies
New technologies such as positron emission tomography (PET) scanning may be indicated in very selective cases, particularly for differentiation of neoplasia and infection.
See Workup for more detail.
Management
Antimicrobial therapy is indicated in virtually all Enterobacter infections. With few exceptions, the major classes of antibiotics used to manage infections with these bacteria include the following:
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Beta-lactams: Carbapenems are the most reliable beta-lactam drugs for the treatment of severe Enterobacter infections; fourth-generation cephalosporins are a distant second choice
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Aminoglycosides: Aminoglycoside resistance is relatively common and varies widely among centers; concerns about potential toxicities and penetration into some body tissues limit their use
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Fluoroquinolones: Resistance to fluoroquinolones is increasing and may be very high in some parts of the world
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Trimethoprim-sulfamethoxazole (TMP-SMZ): Resistance to TMP-SMZ is more common
See Treatment and Medication for more detail.
Background
Enterobacter species, particularly those in the Enterobacter cloacae complex 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, CNS, and ophthalmic infections. [3] Enterobacter species can also cause various community-acquired infections, including UTIs, skin and soft tissue infections, and wound infections, among others. They are one of the ESKAPE pathogens: a group comprised of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) that are capable of 'escaping' the biocidal action of antibiotics and that cause most of the hospital-associated infections in the United States. [4, 5]
The genetic variation (heterogenicity) and biochemical diversity among E cloacae has led to use of the terminology Enterobacter cloacae complex (ECC). [2, 3] Of note, the species formerly known as Enterobacter aerogenes was reassigned to the genus Klebsiella (now known as Klebsiella aerogenes) in 2017 [6] although this reassignment still is debated. Much of the literature regarding Enterobacter species prior to this date includes data attributable to K aerogenes. Nevertheless, conclusions regarding E cloacae complex and other individual species (eg, E cloacae, Enterobacter hormaechei, etc) that may cause human infections remain valid.
Risk factors for nosocomial Enterobacter 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. [7] 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. [8]
These "ICU bugs" cause significant morbidity and mortality, and infection management is complicated by resistance to multiple antibiotics. Multi-drug resistant Enterobacter cloacae complex, especially those resistant to carbapenems, have emerged as a global diversifying threat. [9, 3] Enterobacter species possess inducible beta-lactamases, which are undetectable in vitro but are responsible for resistance during treatment. Physicians treating patients with Enterobacter infections are advised to avoid certain antibiotics, particularly third-generation cephalosporins, because resistant mutants can quickly appear. [10] 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 Enterobacter species, even if routine in vitro antibiotic susceptibility testing has not identified resistance. [11, 12]
Pathophysiology
Enterobacter species rarely cause disease in healthy individuals. This opportunistic pathogen, similar to other members of the Enterobacteriaceae family (in the order Enterobacterales), possesses an endotoxin known to play a major role in the pathophysiology of sepsis and its complications.
Although community-acquired Enterobacter infections occasionally are reported, nosocomial Enterobacter infections are, by far, most common. Patients most susceptible to Enterobacter infections are those who stay in the hospital, especially the ICU, for prolonged periods. [7] Other major risk factors for Enterobacter infection include 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 the patient's gastrointestinal tract, colonization of the skin, or urinary tract) or exogenous, resulting from the ubiquitous nature of Enterobacter species. Multiple reports have incriminated the hands of health care 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. [13]
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 Enterobacter infection that appears sensitive to cephalosporins at diagnosis may quickly develop into a resistant infection during therapy. Carbapenems and cefepime have a more stable beta-lactam ring against the lactamase produced by resistant strains of Enterobacter.
Epidemiology
Frequency
United States
National surveillance programs continually demonstrate that Enterobacter species remain a significant source of morbidity and mortality in hospitalized patients.
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 ICU settings. Enterobacter species represent 3.1% of bloodstream infections in non-ICU wards. Of nearly 75,000 gram-negative organisms collected from ICU patients in the United States between 1993 and 2004, Enterobacter species comprised 13.5% of the isolates. Multidrug resistance increased over time, especially in infections caused by E cloacae. [8, 14]
The National Healthcare Safety Network (NHSN) reported on healthcare-associated infections (HAI) between 2006 and 2007. They found Enterobacter species to be the eighth most common cause of HAI (5% of all infections) and the fourth most common gram-negative cause of HAIs. [15]
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, ranking third after Staphylococcus aureus (18.1%) and P aeruginosa (17%). [7] The corresponding rates among patients in pediatric ICUs were 9.8% for pneumonia, 6.8% for bloodstream infections, and 9.5% for UTIs. [16, 17, 18]
Enterobacter species were also among the most frequent pathogens involved in 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. [10, 19] Carbapenem resistance among Enterobacteriaceae (including Escherichia coli, Klebsiella, and E cloacae complex species) rose significantly in US hospitals from 2001-2011. [20]
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 neonates and debilitated patients in ICUs.
The investigation of a multiclonal outbreak of Enterobacter cloacae infections in a neonatal ICU in France found over 469 gastrointestinally colonized infants, 30 infections including 2 cases of meningitis, and 12 deaths. The infection strains were genetically diverse, supporting the hypothesis of multiple hygiene defects rather than dissemination of a single bacterial clone. Their interventions included several hygienic preventive measures, education of staff, and limiting the use of cephalosporin antibiotics. The outbreak eventually was successfully contained, although direct attribution to the interventions was not conclusive. [21]
The prevalence of Enterobacter resistance to beta-lactam antibiotics, aminoglycosides, trimethoprim-sulfamethoxazole (TMP-SMZ), and quinolones seems to be higher in certain European countries and Israel than in the United States and Canada. Higher rates of Enterobacter resistance to fluoroquinolones and to beta-lactam and cephalosporin antibiotics due to the production of extended-spectrum beta-lactamases have been reported in South America and the Asian and Pacific regions. [22, 23]
In a recent publication from Saudi Arabia, authors assessed epidemiologic patterns, resistance characteristics, and clinical outcomes of E cloacae infections and also assessed the impact of the COVID-19 epidemic on resistance patterns and mortality rates. They found a high number of E cloacae respiratory isolates, possibly due to higher risks with COVID-19 severe respiratory disease and intubation, but that the percentage of resistant isolates fell from 48.36% in 2019 (pre-pandemic) to 38% in 2020 and 37.6% in 2021. The ICU mortality rate was 40.5%. The authors proposed that the decrease in resistant E cloacae isolates during the first 2 years of the COVID-19 epidemic may have been attributable to infection control measures, the use of personal protective equipment by healthcare workers, and decontamination procedures. [24]
Mortality/Morbidity
Enterobacter infections cause considerable mortality and morbidity rates.
Enterobacter species 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 laboratory tests, various surgical and nonsurgical procedures, and powerful and expensive antimicrobial agents. Most importantly, Enterobacter infections that do not directly result in death cause considerable suffering in many patients, most of whom already are afflicted with chronic diseases.
In patients with Enterobacter bacteremia, the most important factor in determining the risk for mortality is 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, ICU admission, prolonged hospitalization, prior surgery, intravascular and/or urinary catheters, immunosuppressive therapy, neutropenia, antibiotic resistance, and inappropriate antimicrobial therapy.
Studies have demonstrated that empirical aminoglycoside use and appropriate initial antibiotic therapy were associated with lower mortality rates, whereas vasopressor use, ICU care, and acute renal failure were associated with higher mortality rates. Independent risk factors for mortality included cephalosporin resistance, trimethoprim-sulfamethoxazole resistance, mechanical ventilation, and nosocomial infection. [25, 26]
Crude mortality rates associated with Enterobacter infections range from 15-87%, but most reported rates range from 20-46%. Attributable mortality rates are reported to range from 6-40%.
E cloacae infection is associated with the highest mortality rate of all Enterobacter infections.
Bacteremia with cephalosporin-resistant Enterobacter species is associated with a 30-day mortality rate that significantly exceeds that of infections with susceptible strains (33.7% vs 18.6%).
Mortality rates associated with Enterobacter pneumonia are higher than those of pneumonia due to many other gram-negative bacilli. These rates range 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 include the extent of the disease as seen on chest radiographs, corticosteroid therapy, isolation of multiple pathogens from lower respiratory tract secretions, and, possibly, treatment with a single antibiotic.
A review of 17 cases of Enterobacter endocarditis reported an overall mortality rate of 44.4%.
Race
Enterobacter infections have no reported or presumed racial predilection.
Sex
The male-to-female ratio of Enterobacter bacteremia is 1.3-2.5:1. This male predominance also is found in the pediatric population.
Age
Enterobacter infections are most common in neonates and in elderly individuals, reflecting the increased prevalence of severe underlying diseases at these age extremes. In the pediatric ICU setting, an age younger than 2.5 years is a risk factor for colonization.
Enterobacter sakazakii, now known as Cronobacter sakazakii, has been reported as a cause of sepsis and meningitis, complicated by ventriculitis, brain abscess, cerebral infarction, and cyst formation. [27] This clinical pattern appears to be specific to C sakazakii in neonates and infants infected with this bacterium. C sakazakii also has been associated with many outbreaks due to contaminated powdered formula for infants. [28, 29]
The taxonomic reclassification of E sakazakii within a new genus "Cronobacter" within the Enterobacteriaceae was proposed in 2007. [30]
Prognosis
The prognosis of E cloacae complex infections depends on numerous variables, including the infection site (eg, bloodstream, meninges, lungs), time to diagnosis and treatment, antimicrobial resistance, and underlying host vulnerabilities. The mortality rate generally is high, similar to infections caused by other invasive gram-negative bacilli.
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Radiograph of an open right tibial fracture in a 21-year-old male marine who was wounded when an improvised explosive device detonated while he was on patrol in Iraq.
