Enterobacter Infections

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. 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.

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:

• Physical examination findings consistent with systemic inflammatory response syndrome (SIRS): Including heart rate that exceeds 90 bpm, a respiratory rate greater than 20, and a temperature above 38°C or below 36°C
• Fever: Occurring in more than 80% of children and adults with Enterobacter bacteremia
• Hypotension and shock: Occur in as many as one third of cases
• Septic shock: Manifested as disseminated intravascular coagulation, jaundice, acute respiratory distress syndrome, and other complications of organ failure
• Purpura fulminans and hemorrhagic bullae
• Ecthyma gangrenosum
• Cyanosis and mottling: Frequently reported in children with Enterobacter bacteremia

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:

• Apprehension
• High fever or hypothermia
• Tachycardia
• Hypoxemia
• Tachypnea
• Cyanosis

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:

• Complete blood count
• Creatinine level
• Electrolyte evaluation
• Fluid analysis, such as cells and differential, proteins, glucose, and, in some cases, pH, lactate dehydrogenase, and amylase; required for pleural, articular, pericardial, peritoneal, and cerebrospinal fluids
• Urine analysis: Always indicated for urinary tract infections (UTIs)

Factors in the microbiologic diagnosis and assessment of Enterobacter infection include the following:

• The most important test to document Enterobacter infections is culture; when the patient presents with signs of systemic inflammation (eg, fever, tachycardia, tachypnea) with or without shock (eg, hypotension, decreased urinary output), blood cultures are mandatory
• 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
• 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) agars

Imaging studies

Studies used in the investigation and management of Enterobacter infections include the following:

• Chest infections: Serial chest radiography, chest ultrasonography, and computed tomography (CT) scanning
• Intra-abdominal infections: CT scanning and ultrasonography
• Endocarditis and intravascular infections: Echocardiography (preferably transesophageal) and nuclear indium scanning
• UTIs: Renal ultrasonography; occasionally, CT scanning and pyelography
• Central nervous system (CNS) and ophthalmic infections: CT scanning and/or magnetic resonance imaging (MRI)
• 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:

• 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
• Aminoglycosides: Aminoglycoside resistance is relatively common and varies widely among centers
• Fluoroquinolones: Resistance to fluoroquinolones is increasing and may be very high in some parts of the world
• Trimethoprim-sulfamethoxazole (TMP-SMZ): Resistance to TMP-SMZ is more common

See Treatment and Medication for more detail.

• References

Background

Enterobacter species, particularly Enterobacter cloacae, 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. Enterobacter species can also cause various community-acquired infections, including UTIs, skin and soft-tissue infections, and wound infections, among others.

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. 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 resistance to multiple antibiotics. 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. 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.^{[1, 2]}

Of note, the species formerly known as Enterobacter aerogenes was reassigned to the genus Klebsiella (now known as Klebsiella aerogenes) in 2017.^[3] Much of the literature regarding Enterobacter species prior to this date includes data attributable to K aerogenes. Nevertheless, conclusions regarding E cloacae complex and the individual species (eg, E cloacae, Enterobacter hormaechei) remain valid.

• References

Pathophysiology

Enterobacter species rarely cause disease in healthy individuals. 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 Enterobacter infections are occasionally 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. Other major risk factors of 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 colonization of the skin, gastrointestinal tract, or urinary tract) or exogenous, resulting from the ubiquitous nature of Enterobacter species. 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 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.

• References

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.^[4]

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.^[5]

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%). The corresponding rates among patients in pediatric ICUs were 9.8% for pneumonia, 6.8% for bloodstream infections, and 9.5% for UTIs.^{[6, 7, 8]}

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.^[9] Carbapenem resistance among Enterobacteriaceae (including Escherichia coli, Klebsiella, and E cloacae complex species) rose significantly in US hospitals from 2001-2011.^[10]

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 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.^{[11, 12]}

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 causing death cause considerable suffering in many patients, most of whom are already afflicted with chronic diseases.

In patients with Enterobacter bacteremia, the most important factor in determining the risk of 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, admission in an ICU, prolonged hospitalization, prior surgery, intravascular and/or urinary catheters, immunosuppressive therapy, neutropenia, antibiotic resistance, and inappropriate antimicrobial therapy.

Recent 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.^{[13, 14]}

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 is also reported 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.^[15] This clinical pattern appears to be specific to C sakazakii in neonates and infants infected with this bacterium. C sakazakii has also been associated with many outbreaks due to contaminated powdered formula for infants.^{[16, 17]}

The taxonomic reclassification of E sakazakii within a new genus "Cronobacter" within the Enterobacteriaceae was proposed in 2007.^[18]

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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 is generally high, similar to infections caused by other invasive gram-negative bacilli.

• References

History

Enterobacter infections do not produce a unique enough clinical presentation to differentiate them clinically from other acute bacterial infections. Consequently, details on the patient history and physical examination findings for each infected body compartment are not provided in this article, with the exception of lower respiratory tract infections and bacteremia. Details regarding similar disease presentations are available throughout Medscape Reference via the links provided in the Differentials section.

Bacteremia

Most cases of Enterobacter bacteremia are nosocomial, frequently acquired in the ICU.

E cloacae, followed by E hormaechei, are the species implicated most frequently in Enterobacter bacteremia cases.

Mixed bacteremia is common (14-53%).

The portal of entry into the bloodstream is frequently unknown, but any infected organ, central line, or arterial catheters may be the primary source of bacteremia.

Symptoms of Enterobacter bacteremia are similar to those of bacteremia due to other gram-negative bacilli.

Lower respiratory tract infections

The clinical presentations caused by Enterobacter lower respiratory tract infections include asymptomatic colonization, tracheobronchitis, pneumonia, lung abscess, and empyema.

As with other respiratory pathogens, chronic obstructive pulmonary disease, diabetes mellitus, alcohol abuse, malignancy, and neurologic diseases are risk factors for the acquisition of lower respiratory tract infections.

Prior antimicrobial therapy may predispose to Enterobacter pneumonia.

Enterobacter species are a significant cause of ventilator-associated pneumonia.

Enterobacter species are major pathogens in early post–lung transplant pneumonia. In most cases, the bacteria are transmitted from the donor.

Symptoms of Enterobacter pneumonia are not specific to these bacteria. Fever, cough, production of purulent sputum, tachypnea, and tachycardia are usually present.

As with infections caused by organisms such as Streptococcus pneumoniae, many Enterobacter infections in elderly debilitated patients do not cause a systemic inflammatory reaction. However, this clinical presentation is by no means benign, and the associated mortality rate is particularly high in this population.

Skin and soft-tissue infections

In most cases, Enterobacter skin and soft-tissue infections are hospital-acquired and include cellulitis, fasciitis, myositis, abscesses, and wound infections.

Enterobacter species can infect surgical wounds in any body site, and these infections are clinically indistinguishable from infections caused by other bacteria.

In 1985, Palmer et al reviewed an outbreak of postsurgical Enterobacter mediastinitis.^[19] Cases varied in severity from fulminant bacteremic infections to less-severe wound infections. The source was unknown, and a case-control analysis suggested that surgical complications and prophylaxis with cephalosporins were associated with the infection. The level of skin and wound colonization was high among patients who underwent cardiac surgery during this outbreak. The outbreak was controlled with barrier isolation, restriction of contacts, and a reduction in the duration of cephalosporin prophylaxis.

Other Enterobacter wound infections have been reported in the literature. Infected body sites have included a posterior spinal wound, burn wounds (many reports), and different types of injuries involving trauma to multiple sites. Some of the infections were polymicrobial. Some authors have noted a trend of traditional wound bacteria (eg, S aureus) being replaced by Enterobacter species and other nosocomial pathogens. Some trauma-related wound infections are acquired before hospital admission. This was the case with agricultural mutilating wounds caused by corn-harvesting machines. Gram-negative rods were predominant (81%), the most common being Enterobacter species and Stenotrophomonas maltophilia.

Enterobacter species occasionally cause community-acquired soft-tissue infections in healthy individuals, including those who sustain war-related or trauma-related injuries.

Endocarditis

A case report described a patient with E cloacae endocarditis on a porcine mitral heterograft. An accompanying literature review disclosed 17 additional cases. Two thirds of the patients had underlying cardiac disease; most had mitral valve infection, and 4 patients had concomitant aortic valve involvement.^[20]

A few more case reports subsequent to this case series have been published in both English and non-English literature.

Urinary tract infections

Enterobacter UTI is indistinguishable from a UTI caused by other gram-negative bacilli.

Pyelonephritis with or without bacteremia, prostatitis, cystitis, and asymptomatic bacteriuria can be caused by Enterobacter species, as with Escherichia coli and other gram-negative bacilli.

Most Enterobacter UTIs are nosocomial and are associated with indwelling urinary catheters and/or prior antibiotic therapy.

Intra-abdominal infections

Enterobacter species may be isolated together with colonic flora in intra-abdominal abscesses or peritonitis following intestinal perforation or surgery.

A frequent cause of Enterobacter involvement is prior digestive-tract colonization by Enterobacter species during hospitalization.

Case reports have described Enterobacter hepatobiliary sepsis, including emphysematous cholecystitis, suppurative cholangitis, and hepatic gas gangrene in a child after liver transplantation. Hemorrhagic necrotizing pancreatitis developed in a 72-year-old woman with obstructive jaundice.

Central nervous system infections

Neonatal meningitis resulting from C sakazakii infection is described in Age.

In 1993, Durand et al published a review of 493 episodes of acute bacterial meningitis.^[21] This study involved patients aged 16 years or older admitted to Massachusetts General Hospital from January 1962 through December 1988. Gram-negative bacilli were the etiologic agents in 4% and 38% of community-acquired and nosocomial meningitis, respectively. In community-acquired infections, Enterobacter was isolated in one of the 9 cases of meningitis caused by gram-negative bacilli (E coli 4 times, Klebsiella species 3 times, and Proteus once) and in 5 of the 57 episodes of nosocomial meningitis (E coli 17 times, Klebsiella species 13 times, Pseudomonas species 6 times, and Acinetobacter species 6 times).

Other series were reported from various countries (United States, Iceland, United Kingdom, Senegal, Brazil). Gram-negative bacilli were not among the 5 most common causes of meningitis in any of these countries.

Ophthalmic infections

Enterobacter species account for a small fraction of postsurgical endophthalmitis and posttraumatic cases.^[22]

Most ophthalmic infections are caused by gram-positive organisms, but Enterobacter species and Pseudomonas species are among the most aggressive pathogens.

Bone and joint infections

Enterobacter species are occasionally implicated in septic arthritis, on both native and prosthetic joints, and can result in osteomyelitis and discitis in adults and children.

Enterobacter bone and joint infections are usually more difficult to cure than those caused by S aureus. The authors have observed relapses that required additional treatment following the initial 6 weeks of intravenous therapy.

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Physical

Bacteremia

Physical examination findings consistent with systemic inflammatory response syndrome (SIRS) include heart rate that exceeds 90 bpm, a respiratory rate of greater than 20, and temperature of greater than 38°C or less than 36°C.

More than 80% of children and adults with Enterobacter bacteremia develop fever.

Hypotension and shock occur in as many as one third of cases.

Disseminated intravascular coagulation, jaundice, acute respiratory distress syndrome, and other organ failures reflect the severity of septic shock.

Purpura fulminans and hemorrhagic bullae usually observed with meningococci or viruses causing hemorrhagic fever may be part of the clinical presentation of Enterobacter bacteremia.

Ecthyma gangrenosum, usually associated with Pseudomonas or Aeromonas bacteremia, may also be observed.

Cyanosis and mottling is frequently reported in children with Enterobacter bacteremia.

Lower respiratory tract infections

The physical manifestations caused by Enterobacter are not specific for infection with these bacteria. Enterobacter lower respiratory tract infections can manifest identically to those caused by S pneumoniae or other organisms.

The physical examination findings may include apprehension, high fever or hypothermia, tachycardia, hypoxemia, tachypnea, and cyanosis. 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.

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Causes

Species of the Enterobactercloacae complex are gram-negative bacilli that belong to the Enterobacteriaceae family. Other members of this family include Klebsiella, Escherichia, Citrobacter,Cronobacter, Serratia, Salmonella, and Shigella species, among many others. Enterobacteriaceae are the most common bacterial isolates recovered from clinical specimens. These bacteria have an outer membrane that contains, among other things, lipopolysaccharides from which lipid-A plays a major role in sepsis. Lipid-A, also known as endotoxin, is the major stimulus for the release of cytokines, which are the mediators of systemic inflammation and its complications.

In the microbiology laboratory, colonies of Enterobacteriaceae appear large, dull-gray, and dry or mucoid on sheep blood agar. All Enterobacteriaceae ferment glucose and, consequently, are able to grow in aerobic and anaerobic atmospheres.

MacConkey agar is a lactose-containing medium that is selective for nonfastidious gram-negative bacilli such as Enterobacteriaceae. Using the enzymes beta-galactosidase and beta-galactoside permeases, the most frequently encountered species of Enterobacter strains activate the pH indicator (neutral red) included in MacConkey agar, giving a pink or red stain to the growing colonies. Klebsiella and Enterobacter species may appear similar as mucoid colonies but can be differentiated with a few specific tests. In contrast to Klebsiella species, Enterobacter organisms are motile, usually ornithine decarboxylase-positive, and urease-negative. E sakazakii (reclassified into the Cronobacter genus in 2007) produces a characteristic yellow pigment.

Six different species comprise the E cloacae complex. Some have never been associated with human infections. The most commonly isolated species include E cloacae and E hormaechei, followed by the rarely encountered Enterobacter asburiae, Enterobacter gergoviae, Enterobacter taylorae, and Enterobacter cancerogenus. Enterobacter aerogenes was renamed K aerogenes in 2017.^[3]

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Laboratory Studies

Microbiological studies

The most important test to document Enterobacter infections is culture.

Direct Gram staining of the specimen is also very 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. The specimen submitted to the microbiology laboratory should represent the infectious process in evolution.

When the patient presents with signs of systemic inflammation (eg, fever, tachycardia, tachypnea) with or without shock (eg, hypotension, decreased urinary output), blood cultures are mandatory. Older and debilitated patients or patients receiving nonsteroidal anti-inflammatory drugs, steroids, or immunosuppressive therapy may be bacteremic in the absence of any sign of inflammation. In addition, hypothermia is a characteristic of particularly severe sepsis.

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) agars. After growth in blood or on agar plates has been confirmed, the bacterial colonies are identified through various, usually automated, methods. When identification of a particular isolate is difficult, newer molecular (rRNA or PCR) methods can be used in certain laboratories.

Blood culture details

Two sets (with one aerobic and one anaerobic bottle in each set) should be obtained 20-30 minutes apart, from 2 different sites (if possible). If the patient has a central venous catheter, one set should be drawn through it. In the adult patient, 8-10 mL of blood should be collected in each bottle. Enterobacteriaceae ferment glucose and should thus grow in both bottles.

Growth in the presence and absence of oxygen is very important early information permitting a presumptive diagnosis of Enterobacteriaceae bacteremia because nonfermentative gram-negative bacilli (eg, Pseudomonas, Acinetobacter, Stenotrophomonas) cannot usually grow in the absence of oxygen.

Lower respiratory tract specimens

Routine Gram staining of sputum is mandatory for every specimen to evaluate the degree of contamination.

A good specimen should show few epithelial cells and many white cells unless the patient is severely neutropenic. In the case of pneumonia, the pathogen (ie, in this article, gram-negative bacilli) should be easily visualized with a high-power lens under oil immersion.

A poor-quality specimen should not be cultured because the identification of organisms that colonize the oropharynx is not helpful for the management of the infection and can cause confusion regarding the cause of the pneumonia. With a lower respiratory tract infection, a significant number of organisms (gram-negative bacilli) should be visible after direct staining. The threshold of optical detection of these bacteria is approximately 10⁵ bacteria/mL. A positive culture result with a negative Gram stain result likely represents colonization rather than infection, at least in untreated patients.

Endotracheal secretions obtained from intubated patients via fluid from bronchoalveolar lavage or bronchoscopy are often contaminated with upper respiratory secretions, and the same caution should be applied in the interpretation of culture results as in the interpretation of sputum specimens. However, bronchoscopy specimens obtained through a protective shield are not contaminated or are only slightly contaminated. Specimens obtained by bypassing the oropharynx (eg, transthoracic biopsy, open lung biopsy) are sterile, and any bacterial growth should be considered significant.

All other specimens

Pus and joint, pleural, pericardial, peritoneal, and cerebrospinal fluids; bile; urine; and biopsy specimens of the skin and subcutaneous tissues, muscles, bone, and any other specimen should be promptly transported to the laboratory for rapid Gram staining and culture (or kept refrigerated for the shortest possible period).

Ophthalmologic specimens, such as those obtained from patients with endophthalmitis, are so small that the frequent recommendation is that they be injected into a blood culture bottle. This practice is also favored for potentially infected ascites fluid, as some evidence in the literature suggests that this method is more sensitive than direct plating on agar.

Intravenous and intra-arterial catheters should also be cultured if catheter sepsis is suggested. The catheter tip is rolled over the agar. Any growth of more than 15 colonies likely represents, according to studies by Maki et al, catheter infection rather than contamination.^[23]

Drugs to include for antimicrobial susceptibility testing

For nonfastidious gram-negative bacilli, potential antimicrobial activity should be tested in vitro. The choice of specific antibiotics to be tested should reflect the availability of each drug in the pharmacy of each institution.

Penicillins should include ampicillin and at least one of the extended-spectrum penicillins (eg, carboxy, ureido, or acylaminopenicillin) such as ticarcillin, mezlocillin, or piperacillin. The addition of ticarcillin-clavulanic acid or piperacillin-tazobactam is optional.

Cephalosporins include a first-generation drug of this class of antibiotics, such as cefazolin, and a third-generation drug with and without Pseudomonas activity, such as ceftriaxone or ceftazidime, as well as the fourth-generation cephalosporin cefepime.

Include at least one carbapenem, usually imipenem or meropenem, in accordance with available pharmaceutical agents in the institution.

Include aminoglycosides, usually gentamicin and tobramycin. Amikacin may be tested primarily or when bacteria show resistance to these 2 drugs.

Include a quinolone, such as ciprofloxacin.

Include TMP-SMZ.

Some laboratories routinely add aztreonam.

A cephamycin, such as cefoxitin, is a useful addition to screen for some specific beta-lactamases, such as those of class C (see Medical Care).

Other antibiotics that may be considered for testing include tigecycline, eravacycline, polymyxin B, colistin, plazomicin, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and ceftazidime-avibactam, especially when particularly resistant organisms are identified.

Methods and results of antimicrobial susceptibility testing

Different methods of testing are available.

One of the most popular is the Kirby-Bauer disk method, which is simple, reliable, and inexpensive but does not quantify the results in terms of minimal inhibitory concentration (MIC).

MIC methods include antimicrobial agar dilution, usually regarded as the criterion standard, or broth (micro) dilution. Manual methods are more time-consuming than disk methods for measuring MIC. Automation for broth microdilution methods is available from different manufacturers.

The results of sensitivity testing are expressed in millimeters of growth inhibition with disk testing or in mcg/mL in MIC testing.

These results are compared to breakpoints issued by the Clinical and Laboratory Standards Institute (CLSI) in order to determine if an organism is susceptible, intermediately susceptible, or resistant to the tested antimicrobial agent. The CLSI may not have breakpoints for some Enterobacter species or for some antibiotics.

Unfortunately, these elegant methods are not flawless, and reports of falsely susceptible (less frequently, falsely resistant) bacteria are by no means rare in daily clinical practice.

Many resistance mechanisms are not detectable with these routine tests, and this is particularly true for the production of some beta-lactamases (see Medical Care).

A good knowledge of the major resistance mechanisms is important for the interpretation of the crude sensitivity results. Consultation with a senior microbiologist and/or an infectious disease specialist should be considered when the organism is resistant to several antibiotics or when additional testing to newer antibiotics is being considered.

Other laboratory studies

Complete blood cell count, creatinine level, and electrolyte evaluation are part of the minimal investigation required for the management of Enterobacter infections.

Fluid analysis (eg, cells and differential, proteins, glucose, and in some cases pH, lactate dehydrogenase, and amylase) is required for pleural, articular, pericardial, peritoneal, and cerebrospinal fluids.

Urine analysis is always indicated for UTIs.

Tests for liver enzymes, creatine kinase, sedimentation rate, C-reactive protein, bone marrow examination, and microscopic examination of stained biopsy specimens are indicated according to the type of infection involved.

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Imaging Studies

Imaging studies are an important part of the investigation and management of Enterobacter infections. Specific studies are chosen based on the organ or systems involved in the infectious process.

For chest infections, serial chest radiography, chest ultrasonography, and CT scanning are useful when pulmonary abscesses, pleural or pericardial effusions, empyema, and/or mediastinitis is a concern.

Intra-abdominal infections may require CT scanning and ultrasonography.

Endocarditis and intravascular infections may require echocardiography, preferably transesophageal. In some situations, nuclear indium scanning may be helpful.

UTIs may require renal ultrasonography. Occasionally, CT scanning and pyelography (ie, intravenous or retrograde) are useful.

Central nervous system and ophthalmic infections may require CT scanning and/or MRI.

Bone and joint infections may require plain radiography. CT scanning and/or MRI studies are helpful in selected cases of soft-tissue infections, osteomyelitis, and septic arthritis. Nuclear medicine studies, bone and gallium scans in particular, are frequently a useful complement to plain radiography. Findings from indium scans or other types of marked white blood cell scans are somewhat more specific for the diagnosis of deep infections than gallium scan, although they may be less sensitive. See the image below.

View Image

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....

New technologies such as positron emission tomography (PET) scans may be indicated in very selective cases, particularly for differentiation of neoplasia and infection.

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Procedures

Procedures indicated for various Enterobacter infections may include the following:

• Removal of central venous catheters within 72 hours of gram-negative bacilli infections (This has been shown to lower the risk of relapse.)
• Surgical or percutaneous drainage of infected collections
• Endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography (MRCP) for biliary obstruction
• Lumbar puncture for evaluation of CNS infections
• Soft-tissue or bone needle biopsy

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Histologic Findings

Along with signs of infection (leukocytic infiltration), histology should reveal the presence of bacterial rods.

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Approach Considerations

Investigate and attempt to eliminate all potential sites of infection (ie, attain good "source control"). For instance, an identified abscess should be drained, or an infected joint should prompt surgical consultation for drainage. Remove any potentially infected invasive devices, such as intravenous or urinary catheters.

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Medical Care

Antimicrobial therapy is indicated in virtually all Enterobacter infections. Considerations for empirical therapy include an assessment regarding potential resistance to antibiotics, the infection site, anticipated achievable tissue concentrations of antibiotic, and predicted antibiotic adverse effects.

With few exceptions, the major classes of antibiotics used to manage infections with the E cloacae complex include the beta-lactams, carbapenems, the fluoroquinolones, the aminoglycosides, and TMP-SMZ. Because most Enterobacter species are either very resistant to many agents or can develop resistance during antimicrobial therapy, the choice of appropriate antimicrobial agents is complicated. Consultation with experts in infectious diseases and microbiology is usually indicated. In 2006, Paterson published a good review of resistance among various Enterobacteriaceae.^[24] Ritchie et al (2009) published a good discussion regarding antibiotic choices for infection encountered in the ICU.^[25]

Newer options include tigecycline, eravacycline, ceftazidime/avibactam, meropenem-vaborbactam, and plazomicin.^[26]

Older options might include intravenous administration of polymyxin B or colistin, drugs that are rarely used, even in large medical centers, and for which standard susceptibility criteria are not available.

Beta-lactams

With rare exceptions, E cloacae complex species are resistant to the narrow-spectrum penicillins that traditionally have good activity against other Enterobacteriaceae such as E coli (eg, ampicillin, amoxicillin) and to first-generation and second-generation cephalosporins (eg, cefazolin, cefuroxime). They also are usually resistant to cephamycins such as cefoxitin. Initial resistance to third-generation cephalosporins (eg, ceftriaxone, cefotaxime, ceftazidime) and extended-spectrum penicillins (eg, ticarcillin, azlocillin, piperacillin) varies but can develop during treatment. The activity of the fourth-generation cephalosporins (eg, cefepime) is fair, and the activity of the carbapenems (eg, imipenem, meropenem, ertapenem, doripenem) is excellent. However, resistance has been reported, even to these agents.

The bacteria designated by the acronym SERMOR-PROVENF (SER = Serratia, MOR = Morganella, PROV = Providencia, EN = Enterobacter, F = freundii for Citrobacter freundii) have similar, although not identical, chromosomal beta-lactamase genes that are inducible. With Enterobacter, the expression of the gene AmpC is repressed, but derepression can be induced by beta-lactams. Of these inducible bacteria, mutants with constitutive hyperproduction of beta-lactamases can emerge at a rate between 10⁵ and 10⁸. These mutants are highly resistant to most beta-lactam antibiotics and are considered stably derepressed.

AmpC beta-lactamases are cephalosporinases from the functional group 1 and molecular class C in the Bush-Jacoby-Medeiros classification of beta-lactamases. They are not inhibited by beta-lactamase inhibitors (eg, clavulanic acid, tazobactam, sulbactam). Ampicillin and amoxicillin, first- and second-generation cephalosporins, and cephamycins are strong AmpC beta-lactamase inducers. They are also rapidly inactivated by these beta-lactamases; thus, resistance is readily documented in vitro and may emerge rapidly in vivo. Jacoby (2009) published a good discussion about the emerging importance of AmpC beta-lactamases.^[27]

Third-generation cephalosporins and extended-spectrum penicillins, although labile to AmpC beta-lactamases, are weak inducers. Resistance is expressed in vitro only with bacteria that are in a state of stable derepression (mutant hyperproducers of beta-lactamases). However, the physician must understand that organisms considered susceptible with in vitro testing can become resistant during treatment by the following sequence of events: (1) induction of AmpC beta-lactamases, (2) mutation among induced strains, (3) hyperproduction of AmpC beta-lactamases by mutants (stable derepression), and (4) selection of the resistant mutants (the wild type sensitive organisms being killed by the antibiotic).

For unknown reasons, extended-spectrum penicillins are less selective than third-generation cephalosporins. The in-therapy resistance phenomenon is less common with carboxy, ureido (eg, piperacillin), or acylaminopenicillins. This phenomenon has been well documented as a cause of treatment failure with pneumonia and bacteremia; however, the phenomenon is rare with UTIs.

The fourth-generation cephalosporin cefepime is relatively stable to the action of AmpC beta-lactamases; consequently, it retains moderate activity against the mutant strains of Enterobacter, hyperproducing AmpC beta-lactamases.

Ceftazidime-avibactam was initially approved in 2015 for the treatment of complicated intra-abdominal infections (cUTI) when given with metronidazole and complicated urinary tract infections (cUTI) due to susceptible organisms including E cloacae. It was subsequently approved for hospital-acquired and ventilator-associated pneumonia. It was also approved in March 2019 for treatment in children older than 3 months with cIAI (given with metronidazole) and cUTI. This antibiotic has been shown both in vitro and in vivo to have activity against multidrug-resistant E cloacae isolates.^{[28, 29]}

Ceftaroline, a "fifth generation" cephalosporin with activity against S aureus and other staphylococci, including methicillin-resistant isolates, has activity and resistance potential against E cloacae complex isolates similar to those of third-generation cephalosporins. Ceftolozane-tazobactam had reliable activity against only wild-type E cloacae complex isolates, but not against ESBL or AmpC-overproducing strains.^[30] Therefore, neither of these antibiotics would be considered useful for empirical treatment of serious Enterobacter infections.

Carbapenems are strong AmpC beta-lactamase inducers, but they remain very stable to the action of these beta-lactamases. As a consequence, no resistance to carbapenems, either in vitro or in vivo, can be attributed to AmpC beta-lactamases. However, Enterobacter species can develop resistance to carbapenems via other mechanisms. The New Delhi metallo-beta-lactamase (NDM-1) has affected Enterobacter species around the world.^{[31, 32, 33]}

The production of extended-spectrum beta-lactamases (ESBLs) has been documented in Enterobacter. Usually, these ESBLs are TEM1 -derived or SHV1 -derived enzymes, and they have been reported since 1983 in Klebsiella pneumoniae, Klebsiella oxytoca, and E coli. Bush et al classify these ESBLs in group 2be and in molecular class A in their beta-lactamase classification.^[34] The location of these enzymes on plasmids favors their transfer between bacteria of the same and of different genera. Many other gram-negative bacilli may also possess such resistant plasmids.

Bacteria-producing ESBLs should be considered resistant to all generations of cephalosporins, all penicillins, and to the monobactams such as aztreonam, even if the in vitro susceptibilities are in the sensitive range according to the CLSI breakpoints. In the past, the CLSI has cautioned physicians regarding the absence of a good correlation with susceptibility when its breakpoints are applied to ESBL-producing bacteria.

The CLSI has published guidelines for presumptive identification and for confirmation of ESBL production by Klebsiella and E coli, guidelines that are often applied to other Enterobacteriaceae. From the above, one can conclude that, when a bacterium of the genus Enterobacter produces ESBL(s) (more than 1 ESBL can be produced by the same bacteria), it does so in addition to the AmpC beta-lactamases that are always present, either in states of inducibility or in states of stable derepression. With stable derepressed mutants, additional ESBL and carbapenemase detection laboratory methods have been published by the CLSI.^[35]

Carbapenems are the most reliable beta-lactam drugs for the treatment of severe Enterobacter infections, and fourth-generation cephalosporins are a distant second choice. The association of an extended-spectrum penicillin with a beta-lactamase inhibitor remains a controversial issue for therapy of ESBL-producing organisms.

Resistance to carbapenems is rare but has been reported and is considered an emerging clinical threat posed by Enterobacter species, as well as by other Enterobacteriaceae.^{[31, 32]} The beta-lactamases first implicated in imipenem resistance were NMC-A and IMI-1, both molecular class A and functional group 2f carbapenemases, which are inhibited by clavulanic acid and then able to hydrolyze all the beta-lactams not associated with a beta-lactamase inhibitor.

In August 2017, meropenem/vaborbactam was FDA approved for complicated urinary tract infections (cUTI) caused by carbapenem-resistant Enterobacteriaceae (CRE). The novel carbapenem/beta-lactamase inhibitor meropenem/vaborbactam (Vabomere) specifically addresses carbapenem-resistant Enterobacteriaceae (CRE) (eg, E coli, K pneumoniae) by inhibiting the production of enzymes that block carbapenem antibiotics, one of the more powerful classes of drugs in the antibiotic arsenal. Bacteria that produce the K pneumoniae carbapenemase (KPC) enzyme are responsible for a large majority of CRE infections in the United States.

The approval was based on data from a phase 3 multicenter, randomized, double-blind, double-dummy study, TANGO-I (n=550) in adults with cUTI, including those with pyelonephritis. The primary endpoint was overall cure or improvement and microbiologic outcome of eradication (defined as baseline bacterial pathogen reduced to < 104 CFU/mL). Data showed about 98.4% of patients treated with intravenous meropenem/vaborbactam exhibited cure/improvement in symptoms and a negative urine culture result, compared with 94.3% of patients treated with piperacillin/tazobactam. About one week posttreatment, approximately 77% of patients treated with meropenem/vaborbactam had symptom resolution and a negative urine culture result, compared with 73% of patients treated with piperacillin/tazobactam.^[36]

Hyperproduction (stable derepression) of AmpC beta-lactamases associated with some decrease in permeability to the carbapenems may also cause resistance to these agents. In vitro low-level ertapenem resistance was not associated with resistance to imipenem or meropenem, but high-level ertapenem resistance predicted resistance to the other carbapenems.^[37]

Metallo-beta-lactamases cause resistance across the carbapenem class, are transmissible, and have been associated with clinical outbreaks in hospitals worldwide. In one reported outbreak of 17 cases of infection (2 due to Enterobacter species), molecular studies demonstrated presence of a gene belonging to bla(VIM-1) cluster.^[38] KPC-type carbapenemases have emerged in New York City.^[24] The new NDM-1 carbapenemase has already rapidly spread to many countries.^[12]

Aminoglycosides

Aminoglycoside resistance is relatively common and varies widely among centers. Amikacin and the new aminoglycoside plazomicin may have better activity than gentamicin or tobramycin but are not usually administered to persons with renal compromise owing to the high potential for toxicity.

Quinolones and TMP-SMZ

Resistance to fluoroquinolones is becoming more common and may be very high in some parts of the world. When susceptibility to fluoroquinolones is demonstrated, ciprofloxacin and levofloxacin would have somewhat better activity than moxifloxacin.

Resistance to TMP-SMZ is more common, and it should be selected only when the susceptibility report is available from the microbiology laboratory and other drugs (eg, carbapenems) are not available for therapy.

Colistin and polymyxin B

These drugs are being used more frequently to treat serious infection caused by multidrug-resistant organisms, sometimes as monotherapy or in combination with other antibiotics. Clinical experience, including documentation of success rates and attributable mortality is broadening.^{[39, 40]} Heteroresistance to colistin was demonstrated in a few Enterobacter isolates collected from ICU patients and was best identified using broth microdilution, agar dilution, or E-test methods.^[41] Polymyxin B was not as active against Enterobacter species as it was against other Enterobacteriaceae but did demonstrate an MIC50 of less than or equal to 1, with 83% of Enterobacter isolates considered susceptible.^[42] One recent in vitro study documented a colistin MIC90 of 2 mcg/mL or less in more than 90% of Enterobacter isolates from Canada.^[43] A study of 89 carbapenem-nonsusceptible Enterobacteriaceae isolates from China showed that polymyxin B was much more active than tigecycline.^[44]

Tigecycline and eravacycline

Although not indicated specifically for Enterobacter pneumonia or bloodstream infections, tigecycline showed excellent in vitro activity against these gram-negative bacilli.^{[45, 46, 47]} In one laboratory study of multidrug-resistant gram-negative bacilli, tigecycline maintained a low MIC against all of the organisms.^[48]

Eravacycline is a new fluorocycline antibiotic in the tetracycline class. It is similar to tigecycline, but with expanded activity.^{[49, 50]} It was approved by the FDA in 2018 for the treatment of intra-abdominal infections caused by susceptible organisms, including E cloacae. Clinical data are not yet extensive but are growing. Neither tigecycline nor eravacycline has FDA approval for use in patients younger than 18 years.

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Surgical Care

Surgical care is indicated as for other sources of infection: drainage or debridement of abscesses, infected collections, or osteomyelitic foci.

In some instances, the clinician must consider this option instead of percutaneous drainage with CT guidance. The severity of the infection and the size of the collection to be drained are among the parameters to consider when choosing the best option for the patient.

For endocarditis, valvular replacement is also indicated, particularly in patients with emboli or intractable heart failure.

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Consultations

Enterobacter species cause severe and frequently life-threatening infections that can originate in virtually any body compartment. Enterobacter infection may warrant consultation with many different subspecialists.

Consultation with an infectious diseases specialist helps in the selection of antimicrobial agents, taking into account the multiple mechanisms of resistance to different classes of antimicrobial agents and the lack of correlation between crude in vitro susceptibility results and true clinical efficacy for most of the beta-lactams.

Intensive care specialists, when appropriate, can help in the management of severe sepsis or septic shock.

General internal medicine and/or medical subspecialists (eg, cardiologists, gastroenterologists, nephrologists, rheumatologists, pulmonologists) may be helpful.

Surgeons may help with the drainage of infected collections, if indicated, as well as with debridement of necrotic tissues.

Consult neonatologists for neonatal sepsis and, possibly, general pediatricians or pediatric subspecialists (including pediatric infectious disease clinicians and pediatric surgeons).

Radiologists and nuclear medicine physicians may help select the best imaging study according to patient's specific problems. Interventional radiologists may be needed to perform percutaneous drainage of infected collections.

A microbiologist can provide valuable assistance by educating clinicians regarding the correct interpretation of susceptibility testing with this organism and selection of further testing, when indicated.

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Medication Summary

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

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Polymyxin B

• Dosing, Interactions, etc.

Clinical Context:  Binds to phospholipids, alters permeability, and damages bacterial cytoplasmic membrane.

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Ciprofloxacin (Cipro)

• Dosing, Interactions, etc.

Clinical Context:  Fluoroquinolone with good activity against pseudomonads and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Among fluoroquinolones, ciprofloxacin has the best activity against the gram-negative bacilli (including Enterobacter). IV and PO formulations available. Oral bioavailability is approximately 80%.

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Levofloxacin (Levaquin)

• Dosing, Interactions, etc.

Clinical Context:  Levofloxacin is an alternative to ciprofloxacin. It has the advantage of once daily dosing, whether administered IV or PO.

Used for pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

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Doripenem (Doribax)

• Dosing, Interactions, etc.

Clinical Context:  Carbapenem antibiotic. Doripenem is a new alternative choice. Has spectrum of activity similar to that of imipenem and meropenem.

Elicits activity against a wide range of gram-positive and gram-negative bacteria. Indicated as a single agent for complicated intra-abdominal infections caused by susceptible strains of E coli, K pneumoniae, P aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus, and Peptostreptococcus micros.

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Imipenem/cilastatin (Primaxin IV)

• Dosing, Interactions, etc.

Clinical Context:  For treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of potential toxicity. DOC for severe Enterobacter infections, except for meningitis and other CNS infections because of some reports indicating higher seizure potential. Hydrolyzed by the renal dehydropeptidase-1. To overcome this urinary inactivation, cilastatin, an inhibitor of this renal enzyme, is administered in equal amounts.

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Meropenem (Merrem IV)

• Dosing, Interactions, etc.

Clinical Context:  Alternative to imipenem for severe Enterobacter infections. Carbapenem of choice for meningitis and for patients at risk for seizures. Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gram-negative bacteria. Not degraded by renal dehydropeptidase-1. Has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem.

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Cefepime (Maxipime)

• Dosing, Interactions, etc.

Clinical Context:  Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage.

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Meropenem/vaborbactam (Vabomere)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for complicated urinary tract infections (cUTI) caused by carbapenem-resistant Enterobacteriaceae (CRE). Vaborbactam is a nonsuicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as K pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity and does not decrease the activity of meropenem against meropenem-susceptible organisms.

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Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except P aeruginosa. Susceptibility of Enterobacter is generally good but varies among centers.

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Ertapenem (Invanz)

• Dosing, Interactions, etc.

Clinical Context:  Bactericidal activity results from inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin-binding proteins. Stable against hydrolysis by various beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. Hydrolyzed by metallo-beta-lactamases.

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Tigecycline (Tygacil)

• Dosing, Interactions, etc.

Clinical Context:  FDA approved for complicated intra-abdominal or skin and soft-tissue infections. A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit and blocks entry of amino-acyl tRNA molecules in ribosome A site. Complicated intra-abdominal infections caused by C freundii, E cloacae, E coli, K oxytoca, K pneumoniae, E faecalis (vancomycin-susceptible isolates only), S aureus (methicillin-susceptible isolates only), S anginosus group (includes S anginosus, S intermedius, S constellatus), B fragilis, B thetaiotaomicron, B uniformis, B vulgatus, C perfringens, and P micros.

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Ceftazidime/avibactam (Avycaz)

• Dosing, Interactions, etc.

Clinical Context:  A new cephalosporin beta-lactamase–inhibitor antibiotic with extended activity against many gram-negative bacilli. Avibactam is a member of a novel class of non–beta-lactam beta-lactamase inhibitors, the diazabicyclooctanes (DBO), acting as a reversible covalent inhibitor. Compared to available inhibitors for clinical use, DBOs are more potent, have a broader spectrum, and have a different mechanism of action. A unique feature of avibactam in contrast to earlier beta-lactamase inhibitors is that avibactam binds reversibly to beta-lactamases, allowing for recyclization and inhibition of additional beta-lactamase molecules. Avibactam effectively inactivates class A (ESBLs and KPC), class C (AmpC), and some class D (eg, OXA-48) beta-lactamases.

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Eravacycline (Xerava)

• Dosing, Interactions, etc.

Clinical Context:  Eravacycline is a fluorocycline antibacterial drug within the tetracycline class. Has expanded activity compared to tigecycline. Available for parenteral administration only. Not approved for use in children.

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Plazomicin (Zemdri)

• Dosing, Interactions, etc.

Clinical Context:  Plazomicin is an aminoglycoside antibacterial indicated for the treatment of complicated urinary tract infections (CUTI), including pyelonephritis, in patients aged 18 years or older. As only limited clinical safety and efficacy data are available, it is reserved for use in patients who have limited or no alternative treatment options. To reduce the development of drug-resistant bacteria and maintain effectiveness of plazomicin and other antibacterial drugs, it should be used only to treat infections that are proven or strongly suspected to be caused by susceptible microorganisms. Dosing adjustments are required in patients with renal impairment.

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Colistimethate (Coly Mycin M)

• Dosing, Interactions, etc.

Clinical Context:  Parenteral formulation indicated for the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli. It is particularly indicated when the infection is caused by sensitive strains of Pseudomonas aeruginosa. Not indicated for Proteus or Neisseria infections. Coly-Mycin M Parenteral has proven clinically effective in the treatment of infections due to the gram-negative organisms Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, and P aeruginosa.

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Class Summary

The antimicrobials most commonly indicated in Enterobacter infections include carbapenems, fourth-generation cephalosporins, aminoglycosides, fluoroquinolones, and TMP-SMZ.

Carbapenems continue to have the best activity against E cloacae, E aerogenes, and other Enterobacter species.^[51] They are not affected by ESBLs. Imipenem-cilastatin and meropenem are used most often. Ertapenem, approved more recently, is gaining clinical experience^[52] but emerging resistance is a growing concern.^[53] Doripenem, approved in the United States in 2007, appears to be as effective as the other carbapenems. In August 2017, meropenem/vaborbactam (Vabomere) was approved for complicated urinary tract infections (cUTIs), including pyelonephritis, caused by susceptible Enterobacteriaceae: E coli, K pneumoniae, and E cloacae species complex.^[36]

First-generation and second-generation cephalosporins are inactive against Enterobacter infections. Third-generation cephalosporins frequently show good in vitro activity against these organisms, but, as explained above, a significant risk of developing full resistance during therapy exists. Resistance develops much less frequently with fourth-generation cephalosporins because they are relatively stable to AmpC beta-lactamase but not (so far) to the less frequently encountered ESBLs (see Medical Care). Third-generation cephalosporins are not indicated for the treatment of severe Enterobacter infections, perhaps with the notable exception of uncomplicated infections.

Fluoroquinolones have good bactericidal activity against gram-negative bacilli; their bioavailability ranges from very good to excellent (with the exception of norfloxacin). Newer quinolones have increased their spectrum toward gram-positive organisms and, in some cases, toward anaerobes. Ciprofloxacin and levofloxacin have the best activity against gram-negative bacilli and should generally be selected over the newer fluoroquinolones if clinically indicated.

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Inpatient & Outpatient Medications

Enterobacter infections that are improving may warrant switch from an intravenous regimen to an oral medication such as a quinolone or TMP-SMZ in accordance with sensitivity testing, when feasible. Ciprofloxacin (500-750 mg PO q12h if renal function is normal) is an acceptable alternative in patients who are able to tolerate oral medication as long as they are not coadministered products that contain divalent cations (calcium or dairy products, iron, magnesium, zinc). There are no guidelines for the treatment of endocarditis caused by enteric gram-negative bacilli.

Some patients with Enterobacter infections may require longer therapy with intravenous antibiotics. In those who meet criteria for home antibiotic therapy, the selected intravenous medication should not usually require more than 3-times-daily infusion. Ertapenem and tigecycline may be considered for such patients in conjunction with antimicrobial susceptibility testing results, infectious disease specialists and home infusion therapy experts. Close therapy while on antibiotics and after stopping antibiotics is essential.

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Deterrence/Prevention

When hospital (ICU) outbreaks of Enterobacter infections occur, isolation and barrier protection should be implemented. Isolation precautions should also be implemented when a multidrug-resistant organism is isolated.

Hand washing or use of alcohol or other disinfecting hand gels by health care workers between contacts with patients prevents transmission of these and other nosocomial bacteria. This is particularly true in ICUs.

Prior antibiotic administration is a major factor for colonization and secondary infections with these multiple-antibiotic–resistant organisms. Clinicians are advised to avoid unnecessary administration of antimicrobial agents or to avoid unnecessary prolonged administration. For surgical prophylaxis, administration of antibiotics for longer than 24 hours is rarely justifiable.

Education programs for physicians and hospital personnel regarding risk reduction for transmission of Enterobacter species and other nosocomial pathogens should be implemented in every hospital. This is usually the responsibility of the Infection Prevention and Control team.

Comprehensive guidelines regarding isolation for and prevention of nosocomial infections and management of infections by multidrug-resistant organisms (eg, ESBL-producing Enterobacter species) in health care settings are available at the Centers for Disease Control Web site (Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007; Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006).

The Centers for Disease Control and Prevention (CDC) has expanded its guidelines for preventing the spread of carbapenem-resistant Enterobacteriaceae (CRE). Noting that most cases of CRE found in the United States have been isolated from patients who received overnight treatment in medical facilities outside the country, the new recommendations are as follows^{[54, 55]} :

• When a CRE is found in a patient who within the previous 6 months had stayed overnight in a non-US health-care facility, the isolate should undergo confirmatory susceptibility testing and the carbapenem resistance mechanism should be determined
• Rectal screening cultures should be ordered for any patient admitted to a health-care facility in the United States after being hospitalized within the previous 6 months in another country; such patients should be placed on contact precautions until the results of the screenings are available.

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Prognosis

See Mortality/Morbidity.

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