Enterobacter Infections

Etiology

Enterobacter is a genus of gram-negative, rod-shaped, facultatively anaerobic bacteria of the Enterobacteriaceae family. It is also described as non-spore-forming, flagella-containing, urease positive, and lactose fermenting.

Virulence of this bacterium depends on a variety of factors. Like other gram-negative enteric bacilli, the bacteria use adhesins to bind to host cells. The presence of a lipopolysaccharide (LPS) capsule can aid the bacteria in avoiding opsonophagocytosis. The LPS capsule can initiate a cascade of inflammation in the host cell and may further lead to sepsis. 

The presence of beta-lactamases in Enterobacter spp. is the primary mechanism of antimicrobial resistance. Beta lactamases can hydrolyze the beta-lactam ring seen in penicillin and cephalosporins. The presence of this enzyme has contributed to an increase in the number of resistant Enterobacter pathogens.[2]

Epidemiology

According to the National Nosocomial Infections Surveillance System, Enterobacter spp. was responsible for approximately five to seven percent of hospital-acquired bacteremias in the United States from 1976-1989. Among isolates in the ICU, it was found that Enterobacter was the third most common pathogen in the respiratory tract, the fourth most common pathogen in surgical wounds, and the fifth most common pathogen in the urinary tract and the bloodstream.[1]

The Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) project analyzed approximately 24,179 cases of nosocomial bloodstream infections in United States Hospitals from 1995-2002. Among monomicrobial bloodstream infections, Enterobacter was found in 4.7% of infections in the ICU but only in 3.1% of infections in non-ICU wards. Enterobacter spp was the fifth most common pathogen isolated in the ICU, and the eighth-most common pathogen isolated in non-ICU wards.[3]

History and Physical

Enterobacter infections are associated with an extensive range of clinical manifestations. The most common clinical syndromes are bacteremia, lower respiratory tract infections, UTIs, surgical site infections, and intravascular device-associated infections. Less commonly occurring infections are nosocomial meningitis, sinusitis, and osteomyelitis. Enterobacter infections can have very similar clinical presentations as other facultative anaerobic gram-negative rod bacterial infections, to the point that they can often be indistinguishable. 

Enterobacter bacteremia has been widely studied. Fever is the most common presentation in this syndrome, as well as systemic inflammatory response (SIRS), hypotension, shock, and leukocytosis, as seen in many other bloodstream presentations.

Enterobacter pneumonia commonly presents with cough, shortness of breath, and consolidations found on a chest x-ray. Enterobacter UTI can present with dysuria, frequency, urgency, and positive leukocyte esterase or nitrites on urinalysis.

Risk factors that predispose to infection include the following:

• Prolonged recent use of antimicrobial treatment
• Immunocompromised states, particularly malignancy and diabetes
• Presence of invasive medical devices 
• Admission to the ICU
• Recent hospitalization or invasive procedure

Evaluation

The gold standard for diagnosing Enterobacter infections is the utilization of cultures. It is recommended that at least two sets of blood cultures be obtained, one aerobic and one anaerobic bottle. MacConkey agar can be used to determine if the specimen is lactose fermenting. Furthermore, indole testing can be performed to differentiate indole negative Klebsiella and Enterobacter and indole positive E. Coli. Enterobacter spp are motile, in contrast to Klebsiella, which is not motile.

Other important laboratory studies include: 

• Gram stain (may be helpful in the rapid determination of gram-negative rods before cultures are available)
• Complete blood count 
• Complete metabolic panel
• Urinalysis with culture

Relevant imaging in accordance with the particular organ system involved can be helpful in guiding management.

Treatment / Management

Antibiotic resistance is a growing problem with regard to treating Enterobacter infections. Possible treatments include carbapenems, beta-lactams, beta-lactamase inhibitors, fluoroquinolones, aminoglycosides, and sulfamethoxazole/trimethoprim.

First and second-generation cephalosporins are generally not effective against Enterobacter infections. Although treatment with a third-generation cephalosporin may be effective in some strains of Enterobacter, treatment with third-generation cephalosporins can lead to multiresistant infection.[4] Third-generation cephalosporins are likely to induce or select derepressed Enterobacter genetic variants of AmpC beta-lactamase, leading to the overproduction of the enzyme and developed resistance. The use of third-generation cephalosporins is not recommended in severe Enterobacter infections due to increased likelihood of resistance, particularly in Enterobacter cloacae and Enterobacter aerogenes, two of the most clinically relevant Enterobacter species. Other mechanisms of resistance include the addition of transferable AmpC gene from plasmids and a mutation in the AmpR repressor.

Fourth-generation cephalosporins are relatively stable among AmpC beta-lactamases, so they are considered an acceptable treatment option if Extended-Spectrum beta-lactamase (ESBL) is not present. ESBL enzymes are able to hydrolyze the oxyimino cephalosporins, which may render third and fourth generation cephalosporins ineffective.[5]

Carbapenems have been shown to be the most potent treatments for multidrug-resistant Enterobacter infections. Meropenem and Imipenem have been shown to be effective against E. cloacae and E. aerogenes. Carbapenems were not generally affected by ESBL in the past. However, resistance has been increasing in recent years. The mechanisms through which Enterobacter becomes resistant to carbapenems involve multiple enzymes that are plasmid-mediated, leading to accessible horizontal transfer and development of widespread resistance.

Possible treatment for carbapenem-resistant Enterobacter (CRE) includes polymyxins, tigecycline, fosfomycin, and carbapenems (used in a double carbapenem regimen).[6] Although it may seem paradoxical, the rationale behind a double carbapenem regimen is that one carbapenem operates as the “sacrificial” medication due to its greater affinity to the carbapenemase, so that the concomitant carbapenem with a lesser affinity can maintain a higher concentration.[7] A combination of antimicrobial agents has been shown to be more effective than monotherapy in cases of CRE in which more serious clinical characteristics are seen, such as septic shock and rapidly progressing disease.[8] (B3)

With regard to CRE bloodstream infections, a combination regimen with a backbone of colistin has been found to be effective. Examples of other drugs that can be used with colistin are carbapenems, tigecycline, and fosfomycin. However, resistance to colistin has been increasing in recent years.[9] It is recommended that colistin-resistant CRE be treated with a combination regimen consisting of a backbone of tigecycline or a combination of two different carbapenems. Examples of other medications that can be used in conjunction with tigecycline include colistin, fosfomycin, and aminoglycosides. Caution must be taken in those with kidney disease since medications such as colistin and aminoglycosides can cause further kidney damage.[10][7][11](A1)

In CRE UTIs in which patients are not critical, aminoglycosides and fosfomycin are treatments of choice as monotherapy if susceptible. [12] Fosfomycin is not recommended for pyelonephritis due to poor oral bioavailability.[13][14] Tigecycline and colistin are not recommended for CRE UTI due to minimal urinary excretion. If a patient with a CRE UTI is in a critical state, combination therapy of carbapenem, in addition to colistin or aminoglycoside, is an acceptable treatment option.[15][16](B2)

Once the patient has improved in the inpatient setting, intravenous antibiotics may be switched to oral antibiotics, and treatment can be completed as an outpatient regimen with fluoroquinolones or sulfamethoxazole/trimethoprim. Enterobacter exhibits intrinsic resistance to macrolides due to resistance to the outer cell envelope’s low permeability.[17]

Treatment for CRE is highly complex, with a wide degree of variability and requires numerous combinations of medications. Experimental drugs are still being studied as resistance continues to persist. Further discussion regarding treatment is outside the scope of this article.

Differential Diagnosis

The differential diagnoses for Enterobacter infection include:

• Sepsis caused by other gram-negative bacilli
• Acute respiratory distress syndrome (ARDS)
• Aspiration pneumonia or pneumonitis
• Pneumonia caused by viruses or other bacteria
• Parapneumonic pleural effusion
• Lung abscess
• Empyema
• Urinary tract infections
• Bacterial prostatitis
• Cellulitis
• Osteomyelitis

Prognosis

The mortality rate for Enterobacter infections is generally high. A study conducted by Kang et al. that analyzed 30-day mortality rates in Enterobacter bacteremia showed that of those receiving appropriate antibiotics, 24.6% died. In those with cephalosporin-resistant strains of Enterobacter, 34.7% died.[18] Similar mortality rates have been shown in Enterobacter infections in which pneumonia, UTI, and soft tissue infections were the primary clinical manifestation.

Complications

All infections from Enterobacter spp. may be complicated by sepsis and septic shock. Enterobacter pneumonia can lead to a possible lung abscess, parapneumonic pleural effusion, empyema, or ARDS.