AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

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

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

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

Pathophysiology

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

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

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

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

Frequency

United States

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

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

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

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

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

International

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

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

Mortality/Morbidity

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

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

Race

• No racial predilection is known or presumed likely.

Sex

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

Age

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

CLINICAL

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History

The clinical presentation of the various Enterobacter infections is not specific enough to permit clinical differentiation of Enterobacter infections 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 the eMedicine journal via the links provided in Differentials.

• Bacteremia
• • Most bacteremia is nosocomial, frequently acquired in the ICU.
  • E cloacae, followed by E aerogenes, are by far the species implicated most frequently.
  • Mixed bacteremia is often observed (14-53%).
  • The portal of entry into the bloodstream frequently is unknown, but any infected organ may be the primary source of bacteremia.
  • Symptoms are similar to bacteremia caused by other gram-negative bacilli.
• Lower respiratory tract infections
• • The span of clinical presentation includes asymptomatic colonization, tracheobronchitis, pneumonia, lung abscess, and empyema.
  • As with other respiratory pathogens, chronic obstructive pulmonary disease, diabetes mellitus, alcohol abuse, malignancy, and neurological diseases are risk factors for the acquisition of lower respiratory tract infections.
  • Prior antimicrobial therapy may predispose patients to Enterobacter pneumonia.
  • Enterobacter is a significant cause of ventilator-associated pneumonia.
  • Enterobacter is a major pathogen in early post–lung transplant pneumonia. In most cases, the bacteria came 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 organisms such as Streptococcus pneumoniae, the absence of a systemic inflammatory reaction is common in elderly debilitated patients. This clinical presentation is by no means benign, and mortality is particularly high in this population.
• Skin and soft tissue infections
• • In most cases, infections are hospital-acquired and include cellulitis, fasciitis, myositis, abscesses, and wound infections.
  • Enterobacter can cause surgical wound infections in any body site, and these infections are clinically indistinguishable from infections caused by other bacteria.
  • An outbreak of postsurgical Enterobacter mediastinitis has been reviewed by Palmer et al. Cases varied in severity (ie, 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 cardiac surgery patients during this outbreak period. Implementing barrier isolation, restricting contacts, and reducing the duration of cephalosporin prophylaxis terminated this outbreak.
  • Other Enterobacter wound infections are reported in the literature. Infected body sites include a posterior spinal wound, burn wounds (many reports), and different types of injuries involving multiple traumatized patients. In some cases, the infections were polymicrobial. Some authors have noted a trend of traditional wound bacteria (eg, S aureus) being replaced by Enterobacter and other nosocomial pathogens. Among traumatized patients, some 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 and Stenotrophomonas maltophilia.
  • Anecdotal reports also demonstrate that Enterobacter occasionally cause community-acquired soft tissues infections in healthy individuals.
• 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.
  • 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, or asymptomatic bacteriuria can be encountered with these bacteria, as with E coli and other gram-negative bacilli.
  • Most of these infections are nosocomial and are associated with indwelling urinary catheters and/or prior antibiotic therapy.
• Intra-abdominal infections
• • Enterobacter can be isolated together with colonic flora in intra-abdominal abscesses or peritonitis following intestinal perforation or surgery.
  • Again, a frequent explanation for Enterobacter involvement is prior digestive tract colonization by Enterobacter during hospitalization.
  • Case reports of Enterobacter hepatobiliary sepsis have been published and include 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 E sakazakii infection is described in Age.
  • Durand et al published a review of 493 episodes of acute bacterial meningitis. The study involved patients aged 16 years or older admitted to Massachusetts General Hospital from January 1962 though 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 once in the 9 cases of meningitis caused by gram-negative bacilli (E coli 4 times, Klebsiella 3 times, and Proteus once) and in 5 of the 57 episodes of nosocomial meningitis (E coli 17 times, Klebsiella 13 times, Pseudomonas 6 times, and Acinetobacter 6 times).
  • Other series were reported from different countries (United States, Iceland, United Kingdom, Senegal, Brazil). In none of these countries was gram-negative bacilli among the 5 most frequent causes of meningitis.
• Ophthalmic infections
• • Enterobacter accounts for a small fraction of cases of postsurgical endophthalmitis.
  • Most ophthalmic infections are caused by gram-positive organisms, but Enterobacter and Pseudomonas are among the most aggressive pathogens.
• Bone and joint infections
• • Enterobacter is occasionally implicated in septic arthritis, either on native or prosthetic joints, and can result in osteomyelitis and discitis in adults and children.
  • These infections are usually more difficult to cure than those caused by S aureus. This author has observed cases of relapse that required longer treatment after the initial 6 weeks of intravenous therapy.

Physical

• Bacteremia
• • Physical examination findings consistent with systemic inflammatory response syndrome (SIRS) include heart rate of greater than 90, respiratory rate of greater than 20, and temperature of greater than 38°C or less than 36°C.
  • Fever develops in more than 80% of children and adults.
  • 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.
  • Ecthyma gangrenosum, usually associated with Pseudomonas or Aeromonas bacteremia, may also be observed.
  • Cyanosis and mottling have frequently been reported in children with bacteremia.
• Lower respiratory tract infections
• • The physical examination findings are not specific for infection with these bacteria, which can manifest identically to infections 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.

Causes

• Enterobacter is a gram-negative bacillus belonging to the Enterobacteriaceae family. Other members of this family include Klebsiella, Escherichia, Citrobacter, Serratia, Salmonella, Shigella species, and many others. Enterobacteriaceae are the most frequent 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 are glucose fermenters 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 red stain to the growing colonies. Klebsiella and Enterobacter may appear similar as mucoid colonies but can be readily differentiated by a few specific tests. In contrast to Klebsiella, Enterobacter organisms are motile, usually ornithine decarboxylase-positive, and urease-negative.
• Many different species comprise the genus Enterobacter. For some, no evidence exists to date that proves they can cause human infections. The most frequently isolated species are E cloacae and E aerogenes, followed by E sakazakii, which produces a characteristic yellow pigment. Other species rarely encountered in the clinic include Enterobacter asburiae, Enterobacter gergoviae, Enterobacter taylorae, Enterobacter hormaechei, and Enterobacter cancerogenus. Enterobacter agglomerans has been removed from the genus Enterobacter and renamed Pantoea agglomerans.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

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• Follow-up
• Miscellaneous
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Lab 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 the majority of these bacteria. The specimen submitted to the microbiology lab should be representative of 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 definitely are necessary.
  • Remember that older and debilitated patients or patients on nonsteroidal anti-inflammatory drugs, steroids, or immunosuppressive therapy may be bacteremic in the absence of any sign of inflammation and that hypothermia is encountered in cases of particularly severe sepsis.
  • In the lab, growth is expected to be detectable in 24 hours or less. Enterobacter grow rapidly on selective (ie, MacConkey) and nonselective (ie, sheep blood) agars.
  • Blood culture details are discussed as follows:
  • • Two sets (with 1 aerobic and 1 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 are glucose fermenters and, thus, should 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 (Pseudomonas, Acinetobacter, Stenotrophomonas, and others) do not usually have the capability to grow in the absence of oxygen.
  • Lower respiratory tract specimens are discussed as follows:
  • • 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 colonizing the oropharynx is not helpful for the management of the infection and can even 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 per milliliter. A positive culture with a negative result after Gram stain likely represents colonization rather than infection, at least in untreated patients.
    • Endotracheal secretions obtained from intubated patients or via bronchoscopy, fluid from bronchoalveolar lavage, or specimens from transtracheal biopsy are also 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 are discussed as follows:
  • • 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 lab for rapid Gram staining and culture (or kept refrigerated for the shortest possible time).
    • 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 infected ascites fluid. 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.
• 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 also a third-generation drug with and without Pseudomonas activity, such as ceftriaxone or ceftazidime.
  • Include a carbapenem, usually imipenem. Test for meropenem if resistance to imipenem is present (mostly for Pseudomonas). Test for ertapenem if the laboratory has the capability.
  • Include the 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 antbiotics that may be considered for testing include tigecycline, polymixin B and colistin, the latter two 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. When manual methods are employed to measure MIC, these techniques are more time-consuming than disk methods. 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), formerly the National Committee for Clinical Laboratory Standards (NCCLS), 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 without flaws, and reports of falsely susceptible (less frequently, falsely resistant) bacteria are by no means a rare event in daily clinical practice.
  • Many resistance mechanisms are not detectable by 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.
• Other lab 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.

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 radiographs, chest ultrasounds, and CT scans are useful when pulmonary abscesses, pleural or pericardial effusions, empyema, or mediastinitis are of concern.
• Intra-abdominal infections may require CT scans and ultrasounds.
• Endocarditis and intravascular infections may require echocardiography, preferably transesophageal. On some occasions, a nuclear indium scan may be helpful.
• UTIs may require renal ultrasounds. Occasionally, a CT scan and pyelography (ie, intravenous or retrograde) may be useful.
• Central nervous system and ophthalmic infections may require a CT scan and/or magnetic resonance imaging (MRI).
• Bone and joint infections may require plain radiographs. CT scan and/or MRI studies are helpful in selected cases of soft tissue infections, osteomyelitis, or 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 findings, although they may be less sensitive.
• New technologies such as positron emission tomography scans may be indicated in very selective cases, particularly for differentiation of neoplasia and infection.

Procedures

• The list of procedures indicated for patients with 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 result in a lower 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

Histologic Findings

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

TREATMENT

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Medical Care

Antimicrobial therapy is indicated in virtually all infections caused by Enterobacter species.

With few exceptions, the major classes of antibiotics used to manage infections with these bacteria are the beta-lactams, the quinolones, the aminoglycosides, and TMP-SMZ.

The choice of appropriate antimicrobial agents is complicated by the fact that the majority of bacteria in this genus are either very resistant to these agents or can develop resistance during antimicrobial therapy. When this occurs, consultation with experts in infectious diseases and microbiology are usually indicated. Newer options include tigecycline. Although it is not indicated specifically for pneumonia or bloodstream infections caused by Enterobacter species, it has excellent in vitro activity against these gram-negative bacilli. 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, E aerogenes, and most of the others 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. Resistance to third-generation cephalosporins (eg, ceftriaxone, cefotaxime, ceftazidime) and to extended-spectrum penicillins (eg, ticarcillin, azlocillin, piperacillin) is variable but can develop during treatment. The activity of the fourth-generation cephalosporins (eg, cefepime) is fair, and, for the carbapenems (eg, imipenem, meropenem, ertapenem), activity 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.
  • These beta-lactamases are 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.
  • 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 by 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 occurs less frequently with carboxy, ureido, 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.
  • 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.
  • The fourth-generation cephalosporins are relatively stable to the action of these beta-lactamases; consequently, they retain moderate activity against the mutant strains of Enterobacter, hyperproducing AmpC beta-lactamases.
  • More recently, the production of extended-spectrum beta-lactamases (ESBLs) has been documented. Usually, these ESBLs are TEM1-derived or SHV1-derived enzymes, and they have been reported since 1983 in K 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. 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.
  • Among Enterobacter, reports indicate that E aerogenes has been the most frequent carrier of ESBL. Unlike the AmpC beta-lactamases, these enzymes are encoded by plasmid DNA and do not possess a molecular mechanism of induction or stable derepression. They are inactivated by the beta-lactamase inhibitors and remain susceptible to cefoxitin (testing cefoxitin is then a useful tool to help differentiate AmpC beta-lactamases from ESBLs).
  • 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.
  • In 1999, this committee 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, ESBL is almost impossible to detect unless molecular methods such as polymerase chain reaction (PCR) or isoelectric focusing (IEF) electrophoresis are used. For inducible strains, no recommendations have been issued by the CLSI for the detection of ESBL (ie, if PCR and IEF electrophoresis are not readily available).
  • Carbapenems are the only 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 for imipenem in strains of E cloacae with a high MIC. The beta-lactamases implicated 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.
  • Hyperproduction (stable derepression) of AmpC beta-lactamases associated with some decrease in permeability to the carbapenems may also cause resistance to these agents.
• Aminoglycosides
• • Aminoglycoside resistance is relatively frequent and varies widely among centers.
  • As with other members of Enterobacteriaceae, this resistance results from the production of different aminoglycoside-inactivating enzymes.
• Quinolones and TMP-SMZ
• • Resistance to fluoroquinolones is relatively rare.
  • Resistance to TMP-SMZ is more frequent.

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-scan 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 when emboli or intractable heart failure is present.

Consultations

This opportunistic pathogen causes severe and frequently life-threatening infections that can originate in virtually any body compartment. Infection warrants 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.
• Consult neonatologists for neonatal sepsis and, possibly, general pediatricians or pediatric subspecialists (including pediatric surgeons).
• Radiologists and nuclear medicine physicians may help select the best imaging study according to patient's specific problems and (radiologists) may be needed to perform percutaneous drainage of infected collections.

MEDICATION

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

Drug Category: Antibiotics

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

Carbapenems have the best activity against E cloacae, E aerogenes, and others.

First-generation and second-generation cephalosporins are inactive against infections caused by Enterobacter. 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 those infections that are uncomplicated.

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 towards gram-positive organisms and, in some cases, towards anaerobes. Ciprofloxacin and levofloxacin have the best activity against gram-negative bacilli and should be generally selected over the newer fluoroquinolones if clinically indicated.

Drug Name	Meropenem (Merrem IV)
Description	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.
Adult Dose	0.5-2 g IV q8-12h
Pediatric Dose	20-40 mg/kg IV q8h
Contraindications	Documented hypersensitivity
Interactions	Probenecid may inhibit renal excretion, thereby increasing levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Dosage adjustments (adult adjustments) CrCl (mL/min) 50-10: 0.5-1 g q12h CrCl <10: 0.5 g/d HD: As for CrCl <10, with an extra 0.5 g after HD Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication

Drug Name	Cefepime (Maxipime)
Description	Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage.
Adult Dose	0.5-2 g IV q8-12h
Pediatric Dose	50 mg/kg IV q8-12h; not to exceed 2 g
Contraindications	Documented hypersensitivity
Interactions	High dose decreases clearance; when used concurrently, aminoglycosides, furosemide, ethacrynic acid, and vancomycin increase nephrotoxic potential
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Dosage adjustments (adult adjustments) CrCl (mL/min) 80-50: 0.5-2 g q12-24h CrCl 50-10: 0.5-2 g/d CrCl <10: 0.25-0.5 g/d HD: as for CrCl <10, with an extra 0.25 g after HD During peritoneal dialysis: 1-2 g q48h Prolonged use may predispose patients to superinfection

Drug Name	Ciprofloxacin (Cipro)
Description	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. Bioavailability is approximately 80%.
Adult Dose	250-750 mg PO q12h; alternatively, 200-400 mg IV q8-12h
Pediatric Dose	25 mg/kg/d PO divided doses q12h; alternatively, 3.2-12.5 mg/kg/d IV divided doses q12h Usually contraindicated in children before puberty unless benefits outweigh risks; limited experience, particularly in children with cystic fibrosis, seems to indicate safety
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosage adjustments (adult adjustments) CrCl (mL/min) <10: 50% of PO or IV dose q12h HD: 0.25-0.5 g PO or 0.2-0.4 g IV q12h During peritoneal dialysis: 0.25-0.5 g PO or 0.2-0.4 g IV q8h In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Trimethoprim-sulfamethoxazole (Septra, Bactrim)
Description	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 generally good but varies among centers.
Adult Dose	160 mg TMP/800 mg SMZ PO q12-24h Alternatively, 3-5 mg/kg IV q6-8h (based on TMP component)
Pediatric Dose	<2 months: Do not administer >2 months: 6-12 mg/kg/d, based on TMP, PO/IV tid/qid
Contraindications	Documented hypersensitivity; megaloblastic anemia resulting from folate deficiency
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosage adjustments (adult adjustments) CrCl (mL/min) 80-50: Recommended IV dose q18h CrCl 50-10: Recommended IV dose q24h CrCl <10: Not recommended HD: 4-5 mg/kg after HD During peritoneal dialysis: 0.16-0.8 g q48h Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in individuals with G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Drug Name	Ertapenem (Invanz)
Description	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.
Adult Dose	1 g qd for 14 d if IV and 7 d if IM; infuse over 30 min if IV CrCl <30 mL/min/1.73 m2: 500 mg IV qd
Pediatric Dose	<3 months: Not established 3 months to 12 years: 15 mg/kg IV q12h; not to exceed 1 g/d >13 years: Administer as in adults
Contraindications	Documented hypersensitivity to drug or amide type anesthetics
Interactions	Probenecid may reduce renal clearance of ertapenem and increase half-life but benefit is minimum and does not justify coadministration
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Pseudomembranous colitis may occur; seizures and CNS adverse reactions may occur; when using with lidocaine to administer intramuscularly, avoid inadvertent injection into blood vessel; decrease dose in renal failure; serious and occasionally fatal hypersensitivity reactions may occur with beta lactams (caution with previous hypersensitivity reactions to penicillin, cephalosporins, other beta lactams, other allergens); do not mix or coinfuse in same IV line as other medications; do not mix with dextrose-containing diluents

Drug Name	Tigecycline (Tygacil)
Description	This drug is FDA approved for complicated intraabdominal 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.
Adult Dose	Infuse each dose over 30-60 min 100 mg IV once, then 50 mg IV q12h Severe hepatic impairment (ie, Child Pugh class C): 100 mg IV once, then 25 mg IV q12h
Pediatric Dose	<18 years: Not established >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration decreases warfarin clearance and increases warfarin Cmax and AUC (monitor aPTT and INR); coadministration of antibiotics with oral contraceptives may decrease contraceptive effect
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in severe hepatic impairment (reduce dose); may adversely effect tooth development; may permit clostridial overgrowth, resulting in antibiotic-associated colitis; may have adverse effects similar to tetracyclines (eg, photosensitivity, pseudotumor cerebri, pancreatitis, antianabolic action)

FOLLOW-UP

Section 8 of 11  

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• Medication
• Follow-up
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In/Out Patient Meds

• When patients are improving and when feasible, some patients could be switched to an oral medication such as a quinolone or TMP-SMZ in accordance with sensitivity testing. Ciprofloxacin (500-750 mg PO q12h) is an acceptable alternative for patients able to tolerate oral medication as long as they are not coadministered products that contain divalent cations (calcium or dairy products, iron, magnesium, zinc.) No documentation exists for managing endocarditis with oral medications.
• Some patients 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 might be considered for such patients in conjunction with infectious disease specialists and home infusion therapy experts.

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 well 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 rarely is 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 control team.

MISCELLANEOUS

Section 9 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to select appropriate antibiotics for treatment is a significant problem with potential legal implications. Selecting agents based only on susceptibility testing reports could be dangerous because rapid resistance could develop during therapy. Consultation with an infectious diseases specialist can be of tremendous help in determining appropriate antibiotic treatment.

Special Concerns

• Bacterial resistance to antibiotics continues to be a significant threat. Many strains of Enterobacter species are already resistant to many antibiotics. The presence of inducible resistance genes on plasmids in other members of the Enterobacteriaceae family is concerning for the possibility of transfer of genes between bacteria, resulting in the development of further resistance in Enterobacter species.
• Good antibiotic prescription, good monitoring of bacterial resistance, and good infection-control practices are among the most important measures that should be in place in each hospital. Laboratory microbiologists, infectious diseases clinicians, pharmacists, hospital epidemiologists, and hospital administrators can assist in reducing the rates of nosocomial infections.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
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Media type:  Radiograph

REFERENCES

Section 11 of 11

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• Introduction
• Clinical
• Differentials
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• Treatment
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• Follow-up
• Miscellaneous
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• References

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