eMedicine Specialties > Infectious Diseases > Bacterial Infections

Enterobacter Infections

Susan L Fraser, MD, Infectious Diseases Service, Walter Reed Army Medical Center; Chairman, Infection Control Committee; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Michael Arnett, MD, Resident, Department of Medicine, Tripler Army Medical Center; Christian P Sinave, MD, Associate Professor, Department of Medical Microbiology and Infectious Diseases, University of Sherbrooke, Canada

Updated: Jan 7, 2010

Introduction

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. 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.

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.

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.^{[1 ]}

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.^{[2 ]}

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.^{[3,4,5 ]}

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.^{[6 ]}

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.^{[7,8 ]}

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.^{[9,10 ]}
• 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 has been reported as a cause of sepsis and meningitis, complicated by ventriculitis, brain abscess, cerebral infarction, and cyst formation.^{[11 ]}This clinical pattern appears to be specific to E sakazakii in neonates and infants infected with this bacterium. E sakazakii has also been associated with many outbreaks due to contaminated powdered formula for infants.^{[12 ]}
• Recently, a taxonomic reclassification of the neonatal pathogen E sakazakii to consist of 5 species within a new genus, " Cronobacter," was proposed.^{[13 ]}

Clinical

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 the eMedicine journal via the links provided in Differentials.

• Bacteremia
  • Most cases of Enterobacter bacteremia are nosocomial, frequently acquired in the ICU.
  • E cloacae, followed by E aerogenes, are by far 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 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.^{[14 ]}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 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.^{[15 ]}
  • 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 E sakazakii infection is described in Age.
  • In 1993, Durand et al published a review of 493 episodes of acute bacterial meningitis.^{[16 ]}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 cases.
  • 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.

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.

Causes

• Enterobacter is a gram-negative bacillus that belongs to the Enterobacteriaceae family. Other members of this family include Klebsiella, Escherichia, Citrobacter, 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 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.
• Many different species comprise the genus Enterobacter. Some have never been associated with human infections. The most commonly isolated species include E cloacae and E aerogenes, followed by E sakazakii (recently reclassified into the Cronobacter genus), 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.

Differential Diagnoses

Workup

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.
  • Blood culture details are discussed as follows:
    • 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 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 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 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 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.^{[17 ]}
• 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.
  • Include at least one carbapenem, usually imipenem, or in accordance with available pharmaceutical agents in the institution.
  • 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 antibiotics that may be considered for testing include tigecycline, polymyxin 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. 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), 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 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.
• 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.

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

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

Histologic Findings

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

Treatment

Medical Care

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 beta-lactams, the fluoroquinolones, the aminoglycosides, and TMP-SMZ. Because most Enterobacter species are either very resistant to these 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.^{[18 ]}

Newer options include tigecycline. Although not indicated specifically for Enterobacter pneumonia or bloodstream infections, tigecycline has excellent in vitro activity against these gram-negative bacilli.^{[19,20,21 ]}In one laboratory study of multidrug-resistant gram-negative bacilli, tigecycline maintained a low MIC against all of the organisms.^{[22 ]}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. Ritchie et al (2009) published a good discussion regarding antibiotic choices for infection encountered in the ICU.^{[23 ]}

• Beta-lactams
  • With rare exceptions, E cloacae, E aerogenes, and most other Enterobacter 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 but may emerge rapidly in vivo. Jacoby (2009) recently published a good discussion about the emerging importance of AmpC beta-lactamases.^{[24 ]}
  • 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.
  • 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 fourth-generation cephalosporins are relatively stable to the action of AmpC 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 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.^{[25 ]}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 species, reports indicate that E aerogenes has been the most common 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, the CLSI 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 and is considered an emerging clinical threat posed by Enterobacter species, as well as by other Enterobacteriaceae. 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.
  • 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.^{[26 ]}
  • 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.^{[27 ]}KPC-type carbapenemases have emerged in New York City.^{[18 ]}
• Aminoglycosides
  • Aminoglycoside resistance is relatively common 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 but may be high in some parts of the world.
  • Resistance to TMP-SMZ is more common.
• 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.^{[28 ][29 ]}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.^{[30 ]}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.^{[31 ]}One recent in vitro study documented a colistin MIC90 of 2 mcg/mL or less in more than 90% of Enterobacter isolates from Canada.^{[32 ]}

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.

Consultations

Enterobacter species cause severe and frequently life-threatening infections that can originate in virtually any body compartment. Enterobacter 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, as well as with debridement of necrotic tissues.
• 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.
• A microbiologist can provide valuable assistance by educating clinicians regarding the correct interpretation of susceptibility testing with this organism.

Medication

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

Antibiotics

The antimicrobials most 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.^{[33 ]}They are not affected by ESBLs. Imipenem-cilastatin and meropenem are used most often. Ertapenem, approved more recently, is gaining clinical experience.^{[34 ]}Doripenem, approved in the United States in 2007, appears to be as effective as the other carbapenems.

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.

Polymyxin B

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

Dosing

Adult

15,000-25,000 U/kg/d IV divided q12h

Pediatric

<2 years: Not established
>2 years: Administer as in adults

Interactions

May increase or prolong effect of neuromuscular blocking agents

Contraindications

Documented hypersensitivity to drug or components of formulation; concurrent use of neuromuscular blockers

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Prolonged use of antibiotics or repeated therapy may result in bacterial or fungal overgrowth of nonsusceptible organisms

Levofloxacin (Levaquin)

In addition to ciprofloxacin, levofloxacin is an alternative choice. 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.

Dosing

Adult

500-750 mg PO/IV qd

Pediatric

<18 years: Not recommended
>18 years: Administer as in adults

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; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Doripenem (Doribax)

Carbapenem antibiotic. Doripenem is a new alternative choice. Has spectrum of activity similar to that of imipenem and meropenem (Fritsche, 2005; Mushtaq, 2004).
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.

Dosing

Adult

500 mg IV q8h infused over 1 h
CrCl 30-49: 250 mg IV q8h
CrCl 11-29: 250 mg IV q12h

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

Carbapenems may decrease valproic acid serum concentration, causing increased seizure risk; probenecid reduces renal clearance of doripenem, resulting in increased doripenem concentration; does not inhibit or induce major CYP450 enzymes

Contraindications

Documented hypersensitivity to doripenem or other carbapenems or demonstrated anaphylactic reactions to beta-lactams

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Clostridium difficile –associated diarrhea has been reported with nearly all antibacterial agents and must be considered in patients with diarrhea; common adverse effects (ie, >5%) include headache, nausea, diarrhea, rash, and phlebitis; decrease dose with renal insufficiency

Imipenem/cilastatin (Primaxin)

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.

Dosing

Adult

500-1000 mg IV q6h; majority of severe infections can be treated with 2 g/d

Pediatric

Age <1 week: 25 mg/kg IV q12h
Age 1-4 weeks: 25 mg/kg IV q8h
Age 4 weeks to 3 months: 25 mg/kg IV q6h
15-25 mg/kg/dose IV q6h suggested for >3 mo
Imipenem should not be used in pediatric CNS infections or in infants with impaired renal function who weigh <30 kg
Fully susceptible organisms: Not to exceed 2 g/d
Moderately susceptible organisms: Not to exceed 4 g/d

Interactions

Coadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose in renal insufficiency (adult adjustments)
CrCl (mL/min) 80-50: 0.5 g IV q6-8h
CrCl 50-10: 0.5 g IV q8-12h
Hemodialysis (HD): 0.25-0.5 g after HD, then q12h
Higher doses significantly increase risk of seizures

Meropenem (Merrem IV)

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.

Dosing

Adult

0.5-2 g IV q8-12h

Pediatric

20-40 mg/kg IV q8h

Interactions

Probenecid may inhibit renal excretion, thereby increasing levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dosage adjustments (adult adjustments)
CrCl (mL/min) 50-10: 0.5-1 g IV q12h
CrCl <10: 0.5 g/d IV
HD: As for CrCl <10, with an extra 0.5 g after HD
Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication

Cefepime (Maxipime)

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

Dosing

Adult

0.5-2 g IV q8-12h

Pediatric

50 mg/kg IV q8-12h; not to exceed 2 g

Interactions

High dose decreases clearance; when used concurrently, aminoglycosides, furosemide, ethacrynic acid, and vancomycin increase nephrotoxic potential

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dosage adjustments (adult adjustments)
CrCl (mL/min) 80-50: 0.5-2 g IV q12-24h
CrCl 50-10: 0.5-2 g/d IV
CrCl <10: 0.25-0.5 g/d IV
HD: as for CrCl <10, with an extra 0.25 g after HD
During peritoneal dialysis: 1-2 g IV q48h
Prolonged use may predispose patients to superinfection

Ciprofloxacin (Cipro)

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%.

Dosing

Adult

250-750 mg PO q12h; alternatively, 200-400 mg IV q8-12h

Pediatric

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

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)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Trimethoprim-sulfamethoxazole (Septra, Bactrim)

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.

Dosing

Adult

160 mg TMP/800 mg SMZ PO q12-24h
Alternatively, 3-5 mg/kg IV q6-8h (based on TMP component)

Pediatric

<2 months: Do not administer
>2 months: 6-12 mg/kg/d, based on TMP, PO/IV tid/qid

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

Contraindications

Documented hypersensitivity; megaloblastic anemia resulting from folate deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Ertapenem (Invanz)

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.

Dosing

Adult

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

<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

Interactions

Probenecid may reduce renal clearance of ertapenem and increase half-life but benefit is minimum and does not justify coadministration

Contraindications

Documented hypersensitivity to drug or amide type anesthetics

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

Tigecycline (Tygacil)

This drug is 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.

Dosing

Adult

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

<18 years: Not established
>18 years: Administer as in adults

Interactions

Coadministration decreases warfarin clearance and increases warfarin C_max and AUC (monitor aPTT and INR); coadministration of antibiotics with oral contraceptives may decrease contraceptive effect

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

Inpatient & Outpatient Medications

• Enterobacter infections that are improving may warrant switch to an oral medication such as a quinolone or TMP-SMZ in accordance with sensitivity testing, when feasible. Ciprofloxacin (500-750 mg PO q12h) 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). No documentation exists for managing endocarditis with oral medications.
• 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 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 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-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).

Prognosis

See Mortality/Morbidity.

Miscellaneous

Medicolegal 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

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.

References

1. Lockhart SR, Abramson MA, Beekmann SE, et al. Antimicrobial resistance among Gram-negative bacilli causing infections in intensive care unit patients in the United States between 1993 and 2004. J Clin Microbiol. Oct 2007;45(10):3352-9. [Medline].

2. Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol. Nov 2008;29(11):996-1011. [Medline].

3. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986-April 1997, issued May 1997. A report from the NNIS System. Am J Infect Control. Dec 1997;25(6):477-87. [Medline].

4. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1990-May 1999, issued June 1999. Am J Infect Control. Dec 1999;27(6):520-32. [Medline].

5. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. Dec 2004;32(8):470-85. [Medline].

6. National Nosocomial Infections Surveillance System. Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Surveillance Report, data summary from January 1996 through December 1997: A report from the National Nosocomial Infections Surveillance (NNIS) System. Am J Infect Control. Jun 1999;27(3):279-84. [Medline].

7. Rossi F, Baquero F, Hsueh PR, et al. In vitro susceptibilities of aerobic and facultatively anaerobic Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: 2004 results from SMART (Study for Monitoring Antimicrobial Resistance Trends). J Antimicrob Chemother. Jul 2006;58(1):205-10. [Medline].

8. Chow JW, Satishchandran V, Snyder TA, et al. In vitro susceptibilities of aerobic and facultative gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: the 2002 Study for Monitoring Antimicrobial Resistance Trends (SMART). Surg Infect (Larchmt). Winter 2005;6(4):439-48. [Medline].

9. Deal EN, Micek ST, Ritchie DJ, et al. Predictors of in-hospital mortality for bloodstream infections caused by Enterobacter species or Citrobacter freundii. Pharmacotherapy. Feb 2007;27(2):191-9. [Medline].

10. Ye Y, Li JB, Ye DQ, et al. Enterobacter bacteremia: Clinical features, risk factors for multiresistance and mortality in a Chinese University Hospital. Infection. Oct 2006;34(5):252-7. [Medline].

11. Gallagher PG, Ball WS. Cerebral infarctions due to CNS infection with Enterobacter sakazakii. Pediatr Radiol. 1991;21(2):135-6. [Medline].

12. Drudy D, Mullane NR, Quinn T, et al. Enterobacter sakazakii: an emerging pathogen in powdered infant formula. Clin Infect Dis. Apr 1 2006;42(7):996-1002. [Medline].

13. Iversen C, Lehner A, Mullane N, Marugg J, Fanning S, Stephan R, et al. Identification of "Cronobacter" spp. (Enterobacter sakazakii). J Clin Microbiol. Nov 2007;45(11):3814-6. [Medline].

14. Palmer DL, Kuritsky JN, Lapham SC, et al. Enterobacter mediastinitis following cardiac surgery. Infect Control. Mar 1985;6(3):115-9. [Medline].

15. Tunkel AR, Fisch MJ, Schlein A, et al. Enterobacter endocarditis. Scand J Infect Dis. 1992;24(2):233-40. [Medline].

16. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. Jan 7 1993;328(1):21-8. [Medline].

17. Maki DG, Weise CE, Sarafin HW. A semiquantitative culture method for identifying intravenous-catheter-related infection. N Engl J Med. Jun 9 1977;296(23):1305-9. [Medline].

18. Paterson DL. Resistance in gram-negative bacteria: enterobacteriaceae. Am J Med. Jun 2006;119(6 Suppl 1):S20-8; discussion S62-70. [Medline].

19. Ratnam I, Franklin C, Spelman DW. In vitro activities of 'new' and 'conventional' antibiotics against multi-drug resistant Gram negative bacteria from patients in the intensive care unit. Pathology. Dec 2007;39(6):586-8. [Medline].

20. Reinert RR, Low DE, Rossi F, et al. Antimicrobial susceptibility among organisms from the Asia/Pacific Rim, Europe and Latin and North America collected as part of TEST and the in vitro activity of tigecycline. J Antimicrob Chemother. Nov 2007;60(5):1018-29. [Medline].

21. Halstead DC, Abid J, Dowzicky MJ. Antimicrobial susceptibility among Acinetobacter calcoaceticus-baumannii complex and Enterobacteriaceae collected as part of the Tigecycline Evaluation and Surveillance Trial. J Infect. Jul 2007;55(1):49-57. [Medline].

22. DiPersio JR, Dowzicky MJ. Regional variations in multidrug resistance among Enterobacteriaceae in the USA and comparative activity of tigecycline, a new glycylcycline antimicrobial. Int J Antimicrob Agents. May 2007;29(5):518-27. [Medline].

23. Ritchie DJ, Alexander BT, Finnegan PM. New antimicrobial agents for use in the intensive care unit. Infect Dis Clin North Am. Sep 2009;23(3):665-81. [Medline].

24. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev. Jan 2009;22(1):161-82, Table of Contents. [Medline].

25. Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother. Jun 1995;39(6):1211-33. [Medline].

26. Woodford N, Dallow JW, Hill RL, et al. Ertapenem resistance among Klebsiella and Enterobacter submitted in the UK to a reference laboratory. Int J Antimicrob Agents. Apr 2007;29(4):456-9. [Medline].

27. Souli M, Kontopidou FV, Papadomichelakis E, et al. Clinical experience of serious infections caused by Enterobacteriaceae producing VIM-1 metallo-beta-lactamase in a Greek University Hospital. Clin Infect Dis. Mar 15 2008;46(6):847-54. [Medline].

28. Pintado V, San Miguel LG, Grill F, et al. Intravenous colistin sulphomethate sodium for therapy of infections due to multidrug-resistant gram-negative bacteria. J Infect. Mar 2008;56(3):185-90. [Medline].

29. Gupta S, Govil D, Kakar PN, Prakash O, Arora D, Das S. Colistin and polymyxin B: A re-emergence. Indian J Crit Care Med. Apr-Jun 2009;13(2):49-53. [Medline].

30. Lo-Ten-Foe JR, de Smet AM, Diederen BM, et al. Comparative evaluation of the VITEK 2, disk diffusion, etest, broth microdilution, and agar dilution susceptibility testing methods for colistin in clinical isolates, including heteroresistant Enterobacter cloacae and Acinetobacter baumannii strains. Antimicrob Agents Chemother. Oct 2007;51(10):3726-30. [Medline].

31. Gales AC, Jones RN, Sader HS. Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001-2004). Clin Microbiol Infect. Apr 2006;12(4):315-21. [Medline].

32. Walkty A, DeCorby M, Nichol K, Karlowsky JA, Hoban DJ, Zhanel GG. In vitro activity of colistin (polymyxin E) against 3,480 isolates of gram-negative bacilli obtained from patients in Canadian hospitals in the CANWARD study, 2007-2008. Antimicrob Agents Chemother. Nov 2009;53(11):4924-6. [Medline].

33. Hawser SP, Bouchillon SK, Hoban DJ, Badal RE. In vitro susceptibilities of aerobic and facultative anaerobic Gram-negative bacilli from patients with intra-abdominal infections worldwide from 2005-2007: results from the SMART study. Int J Antimicrob Agents. Dec 2009;34(6):585-8. [Medline].

34. Bassetti M, Righi E, Fasce R, et al. Efficacy of ertapenem in the treatment of early ventilator-associated pneumonia caused by extended-spectrum beta-lactamase-producing organisms in an intensive care unit. J Antimicrob Chemother. Aug 2007;60(2):433-5. [Medline].

35. Abbott SL, Janda JM. Enterobacter cancerogenus ("Enterobacter taylorae") infections associated with severe trauma or crush injuries. Am J Clin Pathol. Mar 1997;107(3):359-61. [Medline].

36. Alhambra A, Cuadros JA, Cacho J, et al. In vitro susceptibility of recent antibiotic-resistant urinary pathogens to ertapenem and 12 other antibiotics. J Antimicrob Chemother. Jun 2004;53(6):1090-4. [Medline].

37. Caplan ES, Hoyt NJ. Identification and treatment of infections in multiply traumatized patients. Am J Med. Jul 15 1985;79(1A):68-76. [Medline].

38. Clark NM, Patterson J, Lynch JP 3rd. Antimicrobial resistance among gram-negative organisms in the intensive care unit. Curr Opin Crit Care. Oct 2003;9(5):413-23. [Medline].

39. Cosgrove SE, Kaye KS, Eliopoulous GM, et al. Health and economic outcomes of the emergence of third-generation cephalosporin resistance in Enterobacter species. Arch Intern Med. Jan 28 2002;162(2):185-90. [Medline].

40. Cunha BA. Antibiotic Essentials. 9^th ed. Sudbury, MA: Jones & Bartlett; 2010.

41. Cunha BA. Enterobacter: Colonization & infection. Infect Dis Pract. 1999;23:41-3.

42. Cunha BA. Once-daily tigecycline therapy of multidrug-resistant and non-multidrug-resistant gram-negative bacteremias. J Chemother. Apr 2007;19(2):232-3. [Medline].

43. Cunha BA. Pharmacokinetic considerations regarding tigecycline for multidrug-resistant (MDR) Klebsiella pneumoniae or MDR Acinetobacter baumannii urosepsis. J Clin Microbiol. May 2009;47(5):1613. [Medline].

44. Cunha BA, McDermott B, Nausheen S. Single daily high-dose tigecycline therapy of a multidrug-resistant (MDR) Klebsiella pneumoniae and Enterobacter aerogenes nosocomial urinary tract infection. J Chemother. Dec 2007;19(6):753-4. [Medline].

45. Cunha BA, Theodoris AC, Yannelli B. Enterobacter cloacae graft infection/bacteremia in a hemodialysis patient. Am J Infect Control. Apr 2000;28(2):181-3. [Medline].

46. De Champs C, Sirot D, Chanal C, et al. A 1998 survey of extended-spectrum beta-lactamases in Enterobacteriaceae in France. The French Study Group. Antimicrob Agents Chemother. Nov 2000;44(11):3177-9. [Medline].

47. Donati L, Scamazzo F, Gervasoni M, et al. Infection and antibiotic therapy in 4000 burned patients treated in Milan, Italy, between 1976 and 1988. Burns. Aug 1993;19(4):345-8. [Medline].

48. Foster DR, Rhoney DH. Enterobacter meningitis: organism susceptibilities, antimicrobial therapy and related outcomes. Surg Neurol. Jun 2005;63(6):533-7; discussion 537. [Medline].

49. Fritsche TR, Stilwell MG, Jones RN. Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003). Clin Microbiol Infect. Dec 2005;11(12):974-84. [Medline].

50. Fritsche TR, Strabala PA, Sader HS, et al. Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates. Diagn Microbiol Infect Dis. Jul 2005;52(3):209-13. [Medline].

51. Gallagher PG. Enterobacter bacteremia in pediatric patients. Rev Infect Dis. Sep-Oct 1990;12(5):808-12. [Medline].

52. Hanna H, Afif C, Alakech B, Boktour M, et al. Central venous catheter-related bacteremia due to gram-negative bacilli: significance of catheter removal in preventing relapse. Infect Control Hosp Epidemiol. Aug 2004;25(8):646-9. [Medline].

53. Hoffmann H, Sturenburg E, Heesemann J, et al. Prevalence of extended-spectrum beta-lactamases in isolates of the Enterobacter cloacae complex from German hospitals. Clin Microbiol Infect. Apr 2006;12(4):322-30. [Medline].

54. Jiang X, Ni Y, Jiang Y, et al. Outbreak of infection caused by Enterobacter cloacae producing the novel VEB-3 beta-lactamase in China. J Clin Microbiol. Feb 2005;43(2):826-31. [Medline].

55. Kang CI, Kim SH, Park WB, et al. Bloodstream infections caused by Enterobacter species: predictors of 30-day mortality rate and impact of broad-spectrum cephalosporin resistance on outcome. Clin Infect Dis. Sep 15 2004;39(6):812-8. [Medline].

56. Kaye KS, Cosgrove S, Harris A, et al. Risk factors for emergence of resistance to broad-spectrum cephalosporins among Enterobacter spp. Antimicrob Agents Chemother. Sep 2001;45(9):2628-30. [Medline].

57. Larson EL, Cimiotti JP, Haas J, et al. Gram-negative bacilli associated with catheter-associated and non-catheter-associated bloodstream infections and hand carriage by healthcare workers in neonatal intensive care units. Pediatr Crit Care Med. Jul 2005;6(4):457-61. [Medline].

58. Leverstein-van Hall MA, Blok HE, et al. Extensive hospital-wide spread of a multidrug-resistant enterobacter cloacae clone, with late detection due to a variable antibiogram and frequent patient transfer. J Clin Microbiol. Feb 2006;44(2):518-24. [Medline].

59. Liu CP, Wang NY, Lee CM, et al. Nosocomial and community-acquired Enterobacter cloacae bloodstream infection: risk factors for and prevalence of SHV-12 in multiresistant isolates in a medical centre. J Hosp Infect. Sep 2004;58(1):63-77. [Medline].

60. Livermore DM. beta-Lactamases in laboratory and clinical resistance. Clin Microbiol Rev. Oct 1995;8(4):557-84. [Medline].

61. Livermore DM, Oakton KJ, Carter MW, et al. Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent beta-lactamases. Antimicrob Agents Chemother. Oct 2001;45(10):2831-7. [Medline].

62. Luzzaro F, Docquier JD, Colinon C, et al. Emergence in Klebsiella pneumoniae and Enterobacter cloacae clinical isolates of the VIM-4 metallo-beta-lactamase encoded by a conjugative plasmid. Antimicrob Agents Chemother. Feb 2004;48(2):648-50. [Medline].

63. Markowitz SM, Smith SM, Williams DS. Retrospective analysis of plasmid patterns in a study of burn unit outbreaks of infection due to Enterobacter cloacae. J Infect Dis. Jul 1983;148(1):18-23. [Medline].

64. Mushtaq S, Ge Y, Livermore DM. Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized beta-lactamases. Antimicrob Agents Chemother. Apr 2004;48(4):1313-9. [Medline].

65. Paterson DL, Rossi F, Baquero F, et al. In vitro susceptibilities of aerobic and facultative Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: the 2003 Study for Monitoring Antimicrobial Resistance Trends (SMART). J Antimicrob Chemother. Jun 2005;55(6):965-73. [Medline].

66. Pitout JD, Nordmann P, Laupland KB, et al. Emergence of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) in the community. J Antimicrob Chemother. Jul 2005;56(1):52-9. [Medline].

67. Pitout JD, Thomson KS, Hanson ND, et al. Plasmid-mediated resistance to expanded-spectrum cephalosporins among Enterobacter aerogenes strains. Antimicrob Agents Chemother. Mar 1998;42(3):596-600. [Medline].

68. Ristuccia PA, Cunha BA. Enterobacter. Infect Control. Mar 1985;6(3):124-8. [Medline].

69. Rupp ME, Fey PD. Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae: considerations for diagnosis, prevention and drug treatment. Drugs. 2003;63(4):353-65. [Medline].

70. Sader HS, Jones RN, Dowzicky MJ, et al. Antimicrobial activity of tigecycline tested against nosocomial bacterial pathogens from patients hospitalized in the intensive care unit. Diagn Microbiol Infect Dis. Jul 2005;52(3):203-8. [Medline].

71. Sader HS, Jones RN, Stilwell MG, et al. Tigecycline activity tested against 26,474 bloodstream infection isolates: a collection from 6 continents. Diagn Microbiol Infect Dis. Jul 2005;52(3):181-6. [Medline].

72. Sanders CC, Sanders WE Jr. beta-Lactam resistance in gram-negative bacteria: global trends and clinical impact. Clin Infect Dis. Nov 1992;15(5):824-39. [Medline].

73. Sanders WE Jr, Sanders CC. Enterobacter spp.: pathogens poised to flourish at the turn of the century. Clin Microbiol Rev. Apr 1997;10(2):220-41. [Medline].

74. Siegel JD, Rhinehart E, Jackson M, Chiarello L and the HICPAC. Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare SEttings 2007. Centers for Disease Contol. Available at http://www.cdc.gov/ncidod/dhqp/pdf/guidelines/Isolation2007.pdf. Accessed 1 April 12008.

75. Siegel JD, Rhinehart E, Jackson M, Chiarello L, HICPAC. Management of Multidrug-Resistant Organisms In Healthcare Settings, 2006. Centers for Disease Control. Available at http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf. accessed 1 April 2008.

76. Tresoldi AT, Padoveze MC, Trabasso P, et al. Enterobacter cloacae sepsis outbreak in a newborn unit caused by contaminated total parenteral nutrition solution. Am J Infect Control. Jun 2000;28(3):258-61. [Medline].

77. v Dijk Y, Bik EM, Hochstenbach-Vernooij S, v d Vlist GJ, Savelkoul PH, Kaan JA, et al. Management of an outbreak of Enterobacter cloacae in a neonatal unit using simple preventive measures. J Hosp Infect. May 2002;51(1):21-6. [Medline].

78. Watson JT, Jones RC, Siston AM, et al. Outbreak of catheter-associated Klebsiella oxytoca and Enterobacter cloacae bloodstream infections in an oncology chemotherapy center. Arch Intern Med. Dec 12-26 2005;165(22):2639-43. [Medline].

79. Wendt C, Lin D, von Baum H. Risk factors for colonization with third-generation cephalosporin-resistant enterobacteriaceae. Infection. Oct 2005;33(5-6):327-32. [Medline].

80. Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. Aug 1 2004;39(3):309-17. [Medline].

Keywords

Enterobacter infections, Enterobacter cloacae infection, Enterobacter aerogenes infection, Enterobacter sakazakii infection, Enterobacteriaceae infections, E cloacae, E aerogenes, E sakazakii, Enterobacter bacteremia, Enterobacter lower respiratory tract infection, Enterobacter skin infection, Enterobacter soft-tissue infection, Enterobacter urinary tract infection, Enterobacter UTI, Enterobacter endocarditis, Enterobacter intra-abdominal infection, Enterobacter intraabdominal infection, Enterobacter septic arthritis, Enterobacter osteomyelitis, Enterobacter ophthalmic infections, nosocomial Enterobacter infection, Enterobacter pneumonia, Enterobacter taylorae, E taylorae, Enterobacter cancerogenus, E cancerogenus

Contributor Information and Disclosures

Author

Susan L Fraser, MD, Infectious Diseases Service, Walter Reed Army Medical Center; Chairman, Infection Control Committee; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Susan L Fraser, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Michael Arnett, MD, Resident, Department of Medicine, Tripler Army Medical Center
Disclosure: Nothing to disclose.

Christian P Sinave, MD, Associate Professor, Department of Medical Microbiology and Infectious Diseases, University of Sherbrooke, Canada
Christian P Sinave, MD is a member of the following medical societies: American Society for Microbiology and Canadian Infectious Disease Society
Disclosure: Nothing to disclose.

Medical Editor

Maria D Mileno, MD, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Brown University
Maria D Mileno, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International Society of Travel Medicine, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Joseph F John Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: BioMerieux Honoraria Review panel membership; Cubist Honoraria Review panel membership; Pfizer Honoraria Speaking and teaching; Merck Stock dividends stock holdings

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)