Enterobacter infections

Enterobacter is a genus of a common Gram-negative, facultative anaerobic, rod-shaped, non-spore-forming bacteria belonging to the family Enterobacteriaceae. 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. Two of Enterobacter well- known species, Enterobacter aerogenes and Enterobacter cloacae have taken on clinical significance as opportunistic bacteria and have emerged as hospital acquired (nosocomial) pathogens from intensive care patients pathogenic, especially to those who are on mechanical ventilation ¹. Enterobacter infections can include bacteremia, lower respiratory tract infections, skin and soft-tissue infections, urinary tract infections (UTIs), endocarditis, intra-abdominal infections, septic arthritis, osteomyelitis, central nervous system (CNS) infections, and ophthalmic infections. Enterobacter infections can necessitate prolonged hospitalization, multiple and varied imaging studies and laboratory tests, various surgical and nonsurgical procedures, and powerful and expensive antimicrobial agents.

The prevalence of Enterobacter infections in clinical wards has also increased due to the introduction of extended-spectrum cephalosporins and carbapenems in the antibiotic therapy ². The consequence of this antibiotherapy is the emergence of “pan-drug Enterobacter aerogenes isolates” resistant to last-line antibiotics such as carbapenems and also to colistin, for which no therapeutic option was available ³.

Enterobacter causes

Enterobacter species are facultative anaerobic, Gram-stain-negative, and saprophytic microorganisms found in soil, sewage, and as a commensal enteric flora of the human gastrointestinal tract ¹. Enterobacter species have been associated with nosocomial infection in humans, causing bacteremia, endocarditis, septic arthritis, osteomyelitis, skin and soft tissue infections, lower respiratory tract, urinary tract, and intra-abdominal infections ⁴. Some Enterobacter have also been reported plant pathogens ⁵. Antibiotic resistance and its clinical implications have been extensively studied in genus Enterobacter, especially Enterobacter cloacae, which is resistant to cephalosporins, ampicillin, amoxicillin, and cefoxitin ⁶.

Enterobacter aerogenes and Enterobacter cloacae have been reported as important opportunistic and multiresistant bacterial pathogens for humans during the last three decades in hospital wards. These Gram-negative bacteria have been largely described during several outbreaks of hospital-acquired infections in Europe and particularly in France ⁷.

Enterobacter cloacae is ubiquitous in terrestrial and aquatic environments (water, sewage, soil, and food). The species occurs as commensal microflora in the intestinal tracts of humans and animals and is also pathogens in plants and insects. This diversity of habitats is mirrored by the genetic variety of Enterobacter cloacae¹. Enterobacter cloacae and Enterobacter hormaechei are most frequently isolated from human clinical specimens  ⁷. Enterobacter cloacae is also a well-known nosocomial pathogen contributing to bacteremia, endocarditis, septic arthritis, osteomyelitis, and skin/soft tissue infections, and lower respiratory tract- urinary tract and intra-abdominal infections ⁸. Enterobacter cloacae tends to contaminate various medical, intravenous, and other hospital devices ⁹. Nosocomial outbreaks have also been associated with the colonization of certain surgical equipment and operative cleaning solutions ¹⁰. Since a decade, Enterobacter cloacae has been repeatedly reported as a nosocomial pathogen in neonatal units and several outbreaks of infection have been reported ¹¹. Today, variability among strains are less frequent and outbreaks due to clonal Enterobacter cloacae hyper-producing AmpC β-lactamase and extended spectrum β-lactamases carrier isolates are described from neonate specimens, adults urines/feces samples or from environmental samples ¹¹. Enterobacter cloacae has an intrinsic resistance to ampicillin, amoxicillin, first-generation cephalosporins, and cefoxitin owing to the production of constitutive AmpC β-lactamase. It exhibits a high frequency of enzymatic resistance to broad-spectrum cephalosporins.

Thus, Enterobacter cloacae is among the most common Enterobacter species causing only nosocomial infections in the last decade and a lot has been published on the antibiotic-resistance features of these microorganisms. Despite the relevance of Enterobacter cloacae as a nosocomial pathogen, the pathogenic mechanisms and factors contributing in the disease associated with the Enterobacter cloacae complex are not understood yet; this could be due to the scarcity and the dispersion of information available. Its ability to form biofilms and to secrete various cytotoxins (enterotoxins, hemolysins, pore-forming toxins) are important for its pathogenicity ¹. Some genotypes and species, have previously exhibited some associations with clinical specimens, in particular urines and sputum, when clonal outbreaks with members of the Enterobacter cloacae complex were rare (Izdebski et al., 2014). Interestingly, due to the diffusion of most frequent extended spectrum β-lactamases and carbapenemases in this species, Enterobacter cloacae has now become the third broad spectrum Enterobacteriaceae species involved in nosocomial infections after Escherichia coli and Klebsiella pneumoniae ¹².

Enterobacter aerogenes was originally named Aerobacter aerogenes, and was later included in the genus Enterobacter in 1960 ⁷. Enterobacter aerogenes was renamed Klebsiella aerogenes in 2017 ¹³. Enterobacter aerogenes has been involved in significant European outbreak between 1993 and 2003 and is considered as the paradigm of opportunistic bacteria ⁷. Enterobacter aerogenes is isolated as human clinical specimens from respiratory, urinary, blood, or gastrointestinal tract ¹⁴. Epidemiology of this species has been particular in Europe: it has regularly been involved in nosocomial infections outbreaks since 1993, particularly in the Western Europe ¹⁵. Until, 2003, Enterobacter aerogenes was considered as an important emerging multidrug-resistant pathogen, particularly in ICUs ¹⁶.

Enterobacter bacteremia

Most cases of Enterobacter bacteremia are hospital acquired (nosocomial), frequently acquired in the intensive care unit (ICU). Enterobacter cloacae, followed by Enterobacter hormaechei, are the species implicated most frequently in Enterobacter bacteremia cases. Mixed bacteremia is common (14-53%). The portal of entry into the bloodstream is frequently unknown, but any infected organ, central line, or arterial catheters may be the primary source of bacteremia.

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

Enterobacter pneumonia

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.

Enterobacter 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 Enterobactermediastinitis ¹⁷. 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, Staphylococcus aureus) being replaced by Enterobacter species and other nosocomial pathogens. Some trauma-related wound infections are acquired before hospital admission. This was the case with agricultural mutilating wounds caused by corn-harvesting machines. Gram-negative rods were predominant (81%), the most common being Enterobacter species and Stenotrophomonas maltophilia.

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

Enterobacter endocarditis

A case report described a patient with Enterobacter cloacae endocarditis on a porcine mitral heterograft ¹⁸. 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 ¹⁸.

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

Enterobacter 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.

Enterobacter 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.

Enterobacter central nervous system infections

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

In 1993, Durand et al ¹⁹ published a review of 493 episodes of acute bacterial meningitis. 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.

Enterobacter eye infections

Enterobacter species account for a small fraction of postsurgical endophthalmitis and posttraumatic cases ²⁰.

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

Enterobacter 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 Staphylococcus aureus. The authors have observed relapses that required additional treatment following the initial 6 weeks of intravenous therapy.

Enterobacter infections symptoms

Enterobacter infections do not have a clinical presentation that is specific enough to differentiate them from other acute bacterial infections.

Enterobacter bacteremia symptoms

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

Signs of Enterobacter bacteremia include the following:

• Physical examination findings consistent with systemic inflammatory response syndrome: Including heart rate that exceeds 90 bpm, a respiratory rate greater than 20, and a temperature above 100.4 °F (38°C) or below 96.8 °F (36°C)
• Fever: Occurring in more than 80% of children and adults with Enterobacter bacteremia
• Hypotension and shock: Occur in as many as one third of cases
• Septic shock: Manifested as disseminated intravascular coagulation, jaundice, acute respiratory distress syndrome, and other complications of organ failure
• Purpura fulminans and hemorrhagic bullae
• Ecthyma gangrenosum
• Cyanosis and mottling: Frequently reported in children with Enterobacter bacteremia

Physical examination findings consistent with systemic inflammatory response syndrome include heart rate that exceeds 90 bpm, a respiratory rate of greater than 20, and temperature of greater than 100.4 °F (38°C) or less than 96.8 °F (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.

Enterobacter lower respiratory tract infections

Enterobacter lower respiratory tract infections can manifest identically to those caused by Streptococcus pneumoniae or other organisms. The physical examination findings may include the following:

• Apprehension
• High fever or hypothermia
• Fast heart rate (tachycardia)
• Abnormally low level of oxygen in the blood (hypoxemia)
• Abnormally fast or grapid breathing (tachypnea)
• Bluish or greyish color of the skin, nails, lips or around the eyes (cyanosis)

Enterobacter lower respiratory tract infections can manifest identically to those caused by Streptococcus 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.

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.

Enterobacter infections diagnosis

Laboratory studies

The most important test to document Enterobacter infections is culture.

Direct Gram staining of the specimen is also very useful because it allows rapid diagnosis of an infection caused by gram-negative bacilli and helps in the selection of antibiotics with known activity against most of these bacteria. The specimen submitted to the microbiology laboratory should represent the infectious process in evolution.

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

In the laboratory, growth of Enterobacter isolates is expected to be detectable in 24 hours or less. Enterobacter species grow rapidly on selective (ie, MacConkey) and nonselective (ie, sheep blood) agars. After growth in blood or on agar plates has been confirmed, the bacterial colonies are identified through various, usually automated, methods. When identification of a particular isolate is difficult, newer molecular (rRNA or PCR) methods can be used in certain laboratories.

Blood culture details

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

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

Lower respiratory tract specimens

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

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

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

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

All other specimens

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

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

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

Drugs to include for antimicrobial susceptibility testing

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

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

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

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

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

Include a quinolone, such as ciprofloxacin.

Include Trimethoprim and Sulfamethoxazole (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.

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

Methods and results of antimicrobial susceptibility testing

Different methods of testing are available.

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

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

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

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

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

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

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

Other laboratory studies

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

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

Urine analysis is always indicated for UTIs.

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

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

Enterobacter infections treatment

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

Medical care

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

With few exceptions, the major classes of antibiotics used to manage infections with the E cloacae complex include the beta-lactams, carbapenems, the fluoroquinolones, the aminoglycosides, and Trimethoprim and Sulfamethoxazole (TMP-SMZ). Because most Enterobacter species are either very resistant to many agents or can develop resistance during antimicrobial therapy, the choice of appropriate antimicrobial agents is complicated. Consultation with experts in infectious diseases and microbiology is usually indicated. In 2006, Paterson published a good review of resistance among various Enterobacteriaceae ²¹. Ritchie et al ²² published a good discussion regarding antibiotic choices for infection encountered in the ICU.

Newer options include tigecycline, eravacycline, ceftazidime/avibactam, meropenem-vaborbactam, and plazomicin ²³.

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

Beta-lactams

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

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

AmpC beta-lactamases are cephalosporinases from the functional group 1 and molecular class C in the Bush-Jacoby-Medeiros classification of beta-lactamases. They are not inhibited by beta-lactamase inhibitors (eg, clavulanic acid, tazobactam, sulbactam). Ampicillin and amoxicillin, first- and second-generation cephalosporins, and cephamycins are strong AmpC beta-lactamase inducers. They are also rapidly inactivated by these beta-lactamases; thus, resistance is readily documented in vitro and may emerge rapidly in vivo. Jacoby ²⁴ published a good discussion about the emerging importance of AmpC beta-lactamases.

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

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

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

Ceftazidime-avibactam was initially approved in 2015 for the treatment of complicated intra-abdominal infections when given with metronidazole and complicated urinary tract infections (cUTI) due to susceptible organisms including E cloacae. It was subsequently approved for hospital-acquired and ventilator-associated pneumonia. It was also approved in March 2019 for treatment in children older than 3 months with complicated intra-abdominal infections (given with metronidazole) and complicated urinary tract infections. This antibiotic has been shown both in vitro and in vivo to have activity against multidrug-resistant E cloacae isolates ²⁵.

Ceftaroline, a “fifth generation” cephalosporin with activity against S aureus and other staphylococci, including methicillin-resistant isolates, has activity and resistance potential against E cloacae complex isolates similar to those of third-generation cephalosporins. Ceftolozane-tazobactam had reliable activity against only wild-type E cloacae complex isolates, but not against extended spectrum beta-lactamases or AmpC-overproducing strains ²⁶. Therefore, neither of these antibiotics would be considered useful for empirical treatment of serious Enterobacter infections.

Carbapenems are strong AmpC beta-lactamase inducers, but they remain very stable to the action of these beta-lactamases. As a consequence, no resistance to carbapenems, either in vitro or in vivo, can be attributed to AmpC beta-lactamases. However, Enterobacter species can develop resistance to carbapenems via other mechanisms. The New Delhi metallo-beta-lactamase (NDM-1) has affected Enterobacter species around the world ²⁷.

The production of extended-spectrum beta-lactamases (ESBLs) has been documented in Enterobacter. Usually, these extended spectrum beta-lactamases 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 ²⁸. The location of these enzymes on plasmids favors their transfer between bacteria of the same and of different genera. Many other gram-negative bacilli may also possess such resistant plasmids.

Bacteria-producing extended spectrum beta-lactamases 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 Clinical and Laboratory Standards Institute breakpoints. In the past, the Clinical and Laboratory Standards Institute has cautioned physicians regarding the absence of a good correlation with susceptibility when its breakpoints are applied to extended-spectrum beta-lactamases-producing bacteria.

The Clinical and Laboratory Standards Institute has published guidelines for presumptive identification and for confirmation of extended spectrum beta-lactamases 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 extended spectrum beta-lactamases (more than 1 extended spectrum beta-lactamase can be produced by the same bacteria), it does so in addition to the AmpC beta-lactamases that are always present, either in states of inducibility or in states of stable derepression. With stable derepressed mutants, additional extended spectrum beta-lactamases and carbapenemase detection laboratory methods have been published by the Clinical and Laboratory Standards Institute ²⁹.

Carbapenems are the most reliable beta-lactam drugs for the treatment of severe Enterobacter infections, and fourth-generation cephalosporins are a distant second choice. The association of an extended-spectrum penicillin with a beta-lactamase inhibitor remains a controversial issue for therapy of extended spectrum beta-lactamase-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 ²⁷. The beta-lactamases first implicated in imipenem resistance were NMC-A and IMI-1, both molecular class A and functional group 2f carbapenemases, which are inhibited by clavulanic acid and then able to hydrolyze all the beta-lactams not associated with a beta-lactamase inhibitor.

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

The approval was based on data from a phase 3 multicenter, randomized, double-blind, double-dummy study, TANGO-I (n=550) in adults with cUTI, including those with pyelonephritis. The primary endpoint was overall cure or improvement and microbiologic outcome of eradication (defined as baseline bacterial pathogen reduced to < 104 CFU/mL). Data showed about 98.4% of patients treated with intravenous meropenem/vaborbactam exhibited cure/improvement in symptoms and a negative urine culture result, compared with 94.3% of patients treated with piperacillin/tazobactam. About one week posttreatment, approximately 77% of patients treated with meropenem/vaborbactam had symptom resolution and a negative urine culture result, compared with 73% of patients treated with piperacillin/tazobactam ³⁰.

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 ³¹.

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 ³². KPC-type carbapenemases have emerged in New York City ²¹. The new NDM-1 carbapenemase has already rapidly spread to many countries ³³.

Aminoglycosides

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

Quinolones and Trimethoprim and Sulfamethoxazole (TMP-SMZ)

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

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

Colistin and polymyxin B

These drugs are being used more frequently to treat serious infection caused by multidrug-resistant organisms, sometimes as monotherapy or in combination with other antibiotics. Clinical experience, including documentation of success rates and attributable mortality is broadening ³⁴. 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 ³⁵. 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 ³⁶. One recent in vitro study documented a colistin MIC90 of 2 mcg/mL or less in more than 90% of Enterobacter isolates from Canada ³⁷. A study of 89 carbapenem-nonsusceptible Enterobacteriaceae isolates from China showed that polymyxin B was much more active than tigecycline ³⁸.

Tigecycline and eravacycline

Although not indicated specifically for Enterobacter pneumonia or bloodstream infections, tigecycline showed excellent in vitro activity against these gram-negative bacilli ³⁹. In one laboratory study of multidrug-resistant gram-negative bacilli, tigecycline maintained a low MIC against all of the organisms ⁴⁰.

Eravacycline is a new fluorocycline antibiotic in the tetracycline class. It is similar to tigecycline, but with expanded activity ⁴¹. It was approved by the FDA in 2018 for the treatment of intra-abdominal infections caused by susceptible organisms, including E cloacae. Clinical data are not yet extensive but are growing. Neither tigecycline nor eravacycline has FDA approval for use in patients younger than 18 years.

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.

Enterobacter infections prognosis

The prognosis of Enterobacter cloacae complex infections depends on numerous variables, including the infection site (eg, bloodstream, meninges, lungs), time to diagnosis and treatment, antimicrobial resistance, and underlying host vulnerabilities. The mortality rate is generally high, similar to infections caused by other invasive gram-negative bacilli.

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