Enterobacter species

Authors: Maria Virginia Villegas, M.D., John P. Quinn, M.D.


Enterobacter species are motile aerobic gram negative bacilli belonging to the family Enterobacteriaceae. The major species areEnterobacter cloacaeE. aerogenes and E. agglomerans. They first achieved wide notoriety as pathogens in 1976 following a nationwide outbreak of septicemia in 378 patients at 25 hospitals resulting from contaminated intravenous solutions (36). Because they can replicate in glucose-containing parental fluids, they continue to cause sporadic outbreaks of this type (56).  


Enterobacter infections are increasing in frequency, particularly in intensive care units (ICUs). Using data from the National Nosocomial Infection Surveillance (NNIS) survey from the Centers for Disease Control (CDC), collected between 1992 and 1999, Fridkin (19) reported that Enterobacter was the fifth leading cause of ICU infections in the United States and third most common cause of nosocomial pneumonia overall.  

 In early studies of the epidemiology of Enterobacter infections, emphasis was placed on horizontal transmission in hospitals. A landmark study in 1987 by Flynn and colleagues (18) emphasized the importance of Enterobacter arising from a patient’s endogenous gut flora causing subsequent infection. In this study of 87 patients undergoing cardiac surgery, all patients underwent surveillance cultures before and after surgery. Cefazolin prophylaxis was administered to all patients. 23% of patients were colonized on admission and 49% of patients were colonized by 72 hours after surgery. Of those colonized 72% had increased numbers of organisms isolated following cefazolin prophylaxis. Of 12 nosocomial infections due to Enterobacter in this group of patients, 9 were due to strains detected colonizing the gut preoperatively. Subsequent studies have shown that prophylaxis with second and third generation cephalosporins has been associated with selection of multiresistant Enterobacter.

 Enterobacter may also spread from patient to patient due to inadequate attention to infection control measures, especially hand-washing. In a study employing a consensus PCR technique for molecular typing of strains, Davin-Regli and colleagues (10) studied 185 clinical isolates of E. aerogenes collected from two ICU’s over a one-year period from a hospital in France. A ubiquitous clone was found to be responsible for two- thirds of epidemiologically related transmissions in these units.

 Enterobacter is well adapted to cause nosocomial infections, as it is ubiquitous in the environment and can survive on skin and dry surfaces as well as replicate in contaminated fluids. Numerous outbreaks have been described, including infections due to contaminated enteral feedings (52), humidifiers and respiratory therapy equipment (57) and hydrotherapy water in a burn unit (38).  

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Like other enteric gram-negative rods, Enterobacter species cause a wide variety of nosocomial infections, including those affecting the lungs, urinary tract, intrabdominal cavity and intravascular devices. E. sakazakii causes neonatal sepsis with meningitis (439).  


This organism is easy to isolate from clinical specimens and biochemical tests readily separate it from other members of theEnterobacteraceae family.  


Like other enteric gram-negative rods, Enterobacter species are endowed with a number of virulence factors including adhesions, endotoxin, and siderophones to acquire iron (reviewed in reference 16).  


In a report of 33,869 gram-negative isolates (16.1% Enterobacter) from 396 ICUs in the United States sampled between 1990 and 1993, the Intensive Care Unit Surveillance Study, emerging resistance to extended-spectrum cephalosporins was a problem in bothEnterobacter and Klebsiella (25). A follow-up study from the same investigators analyzed 35,790 isolates from ICUs in the United States sampled between 1994 and 2000 (40). In this later collection of organisms, the prevalence of resistance to third generation cephalosporins in Enterobacter was quite stable at 37%. Likewise, resistance to aminoglycosides and carbapenems remained infrequent. The important observation from the more recent data set was a significant increase in the prevalence of resistance to fluoroquinolones in Enterobacter,Klebsiella and Pseudomonas aeruginosa (See Table 1). An analysis of antibiotic usage data was supplied by IMS Healthcare Inc., Westport, CT. This data revealed a highly significant association between the use of fluoroquinolones and resistance to quinolones in gram-negative rods, particularly in the case of Pseudomonas, but also for Klebsiella and Enterobacter.

As shown in Table 2, there was significant cross-resistance noted in EnterobacterP. aeruginosa and K pneumoniae isolates in this survey. In all three organisms, ciprofloxacin resistant strains were significantly more likely to be resistant to gentamicin, amikacin, ceftazidime and imipenem as compared to susceptible stains. This cross-resistance complicates selection of appropriate empiric therapy of multiresistant strains.

 A report from eight hospitals in the United States participating in the NNIS System under the auspices of the Centers for Disease Control analyzed resistance rates among Enterobacter isolates from outpatients and inpatients (3). A clear gradient of increasing ceftazidime resistance rates was noted. The prevalence of ceftazidime resistance was 12% among community isolates, versus 26% among nosocomial isolates. Within these hospitals, resistance rates were consistently higher among ICU isolates (36% versus 26%).  

Mechanisms of Beta Lactam Resistance in Enterobacter

The saga of Enterobacter as a nosocomial pathogen is closely linked to the logarithmic increase in the use of extended-spectrum cephalosporins in the 1980’s. A series of reports emphasized the proclivity of members of this genus to acquire broad beta-lactam resistance during therapy with extended-spectrum cephalosporin’s (7,8,48).  

An illustrative paper is the work of Chow and colleagues (7) reporting 129 cases of Enterobacter bacteremia at six medical centers in the United States. The mean age of infected patients was 59 years. Almost all patients had concomitant illnesses predisposing toEnterobacter sepsis. For example, 42% of patients had undergone recent major surgery and 40% were mechanically ventilated. 29% of the strains were resistant to all beta-lactams other than carbapenems when first isolated in the laboratory. As shown in Table 3, 36 of 37 resistant isolates came from patients exposed to prior antibiotic therapy. In two thirds of those cases, prior therapy had included an extended-spectrum cephalosporin. This difference was highly statistically significant compared to other agents.  

As shown in Table 4, an additional six patients acquired broad beta-lactam resistance during therapy with an extended-spectrum cephalosporin. Five of these six patients were receiving concomitant aminoglycoside therapy. This high incidence compared unfavorably to zero of 50 patients receiving other beta-lactams (e.g. imipenem or broad-spectrum penicillins). In this study, infections due to a multiresistant strain were associated with a mortality rate twice that associated with those due to susceptible strains (32 vs 16%).  

In each case of emergence of resistance during therapy, DNA typing techniques demonstrated strain identity. Post therapy resistant isolates produced up to 5000 fold more chromosomal beta-lactamase activity than susceptible pre-therapy isolates.  

This observation has been made in numerous other studies (15). Therapy with an extended-spectrum cephalosporin often selects for mutants which hyperproduce type I chromosomal beta-lactamase. These mutants occur spontaneously at frequencies of about 107. For example, Jacobson and colleagues (27) demonstrated broad resistance to beta-lactams in 31% of Enterobacter clocae in their hospital and showed that prior therapy with an extended-spectrum cephalosporin was responsible for much of this resistance, not only in Enterobacter, but also among other type-1-beta-lactamase producing pathogens (e.g. Pseudomonas aeruginosaSerratia marcescens and Citrobacterspecies).  

The molecular biology of this phenomenon is quite interesting and has been the subject of detailed studies by a number of investigators over a 15-year period.  The interested reader is referred to the recent excellent review by Jacobs (26) for more details. We will review it briefly here. In many gram-negative bacteria, the inducible beta-lactamase gene AmpC is transcriptionally controlled by a regulator encoded by AmpR, belonging to the lysR family of transcriptionally regulators. Mutations in another locus, AmpD, result in constitutive hyperproduction of the AmpC beta-lactamase even in the absence of inducers, such as beta-lactam antibiotics. These mutants therefore are highly resistant to these compounds. Another gene required for induction of beta-lactamases is AmpG, which encodes an AmpG transmembrane protein. A model has been described which postulates a direct link between beta-lactamase induction and cell wall metabolism. AmpG and AmpD have been shown to be required for cell wall recycling. In this model, the first step is the degradation of murein by specific cell wall hydrolases to yield a muropeptide. This muropeptide is then transported in the cytoplasm by the permease AmpG where its hydrolyzed by AmpD. Purified AmpR in the absence of any effector directs AmpC transcription. This system has been shown to operate in organisms that have a non-inducible beta-lactamase like E.coli, which strongly suggests that the system functions as a means of monitoring cell wall metabolism, integrating a proper balance between synthesis and degradation during bacterial growth.  

Plasmid-mediated extended-spectrum beta-lactamases (ESBLs) are responsible for the explosive rise in the prevalence of extended-spectrum cephalosporin resistance in Klebsiella and E. coli (28). These enzymes have been detected in Enterobacter. The prevalence appears to be highly variable from country to country. As a general observation, they are uncommon in the United States. Pitout et al (45) have described them in sporadic isolates from Richmond, VA. In contrast, they are much more common in some other parts of the world. For example, a study from Greece (55) described ESBLs in 25% of Enterobacter aerogenes isolates and 58% of Enterobactercloacae isolates tested. These organisms had a SHV type beta-lactamase. Investigators in France have described a relatively high prevalence of these enzymes in that country. For example, Neuborth et al (41) have described an epidemic strain type in France of TEM-24 producing strains of Enterobacter. Approximately 50% of French isolates tested are ESBL producers (12).  

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Drug of Choice  

The incidence of nosocomial infections due to Enterobacter is rising and broad resistance to third generation cephalosporins, penicillins and quinolones is an increasing problem. A number of agents remain effective for treatment. Among the beta-lactams, the fourth generation cephalosporins and carbapenems are the most attractive options. Aminoglycosides retain good activity but usually require combination with another agent. Quinolones are highly active against most strains, but emerging resistance is a major concern. Trimethoprim-sulfamethoxazole is under-utilized as therapy of Enterobacter infections.

Beta-Lactams and Extended Spectrum Cephalosporins

All of the so-called "third generation" cephalosporins and the monobactams (e.g. aztreonam) have approximately the same risk of emergence of resistance during therapy of Enterobacter infections. The data on preventing this type of resistance by employing concomitant aminoglycoside therapy is mixed. Jacobson and colleagues (27) found a lower incidence of emergence of resistance to extended-spectrum cephalosporins among patients treated with concomitant aminoglycoside therapy, while Chow and co-workers did not (7).  

newer group of broad spectrum cephalosporins, the so-called "fourth generation" compounds, (e.g. cefepime and cefpirome) usually retain their activity against Enterobacter strains resistant to third generation cephalosporins (51). The basis for this retained activity is 1) faster penetration through outer membrane porin proteins, 2) superior stability to chromosomal beta-lactamases, and 3) enhanced binding to critical penicillin-binding proteins in Enterobacter as compared to older cephalosporins (5,6,21).  

Sanders et al (49) described successful therapy with cefepime of 17 infections due to Enterobacter strains resistant to third generation cephalosporins. These patients had infections at a variety of sites. All patients responded clinically and bacteriologic eradication was documented in 88%.

Cefpirome is structurally similar to cefepime and has roughly comparable activity against Enterobacter strains, including those displaying resistance to third generation cephalosporins (29). There is less data available on clinical efficacy of this agent against multiresistant gram negative pathogens.

In vitro selection of resistance to fourth generation cephalosporins requires two separate mutations, namely loss of a porin protein effecting the permeability of the cell wall to these agents as well as overproduction of AmpC beta-lactamase. Therefore, in in vitro systems, the mutation rate for fourth generation cephalosporins is lower than that for third generation cephalosporins. On a cautionary note, occasional clinical isolates with both of these mutations have been recovered from patients and may be associated with treatment failure.  

Broad Spectrum Penicillins

Piperacillin is slightly less active than extended-spectrum cephalosporins against Enterobacter; in the ISS study, 63% were susceptible to ceftazidime vs 60% to piperacillin. In the Chow study, no patient receiving piperacillin experienced treatment failure due to emergence of resistance (17). In contrast, the work of Jacobson and colleagues reported a statistically significant association of prior piperacillin therapy with broad beta-lactam resistance.

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Carbapenems display superb activity against a wide variety of enteric gram negative pathogens, including Enterobacter(43). Strains of EnterobacterCitrobacter, and Pseudomonas aeruginosa which are resistant to extended-spectrum cephalosporins on the basis of hyperproduction of type I beta-lactamase typically remain susceptible to carbapenems.

Resistance to carbapenems in Enterobacter is rare (1% of NNIS isolates in 1999) (19), presumably because Enterobacterisolates require two separate mutations to acquire carbapenem resistance: loss of porin proteins plus hyperproduction of beta-lactamase (34). Carbapenem resistance among Enterobacter isolates does not appear to be increasing over time.

In the series of Chow et al none of seventeen patients receiving imipenem for Enterobacter bacteremia had resistant organisms emerge during therapy. Meropenem has activity comparable to imipenem against Enterobacter and has proven effective in the therapy of these infections (9,14).

There are a number of new carbapenem and penem agents in development that have excellent activity against Enterobacter.Ertapenem is a new carbapenem with an extended serum half-life that has superb activity against enteric pathogens including Enterobacter(35). Of note, this agent has limited activity against nonfermenters like P. aeruginosa and Acinetobacter.  


In the survey of 4999 isolates of Enterobacter collected from 396 ICUs in the United States between 1994 and 2000, 98% were susceptible to amikacin and 92% were susceptible to gentamicin and tobramycin. These rates were stable over this time period. In the Chow study only one of 89 patients receiving aminoglycoside therapy failed treatment due to emergence of resistance during therapy (7). Aminoglycoside resistance in Enterobacter is usually due to plasmid-mediated aminoglycoside modifying enzymes.

Special Situations 


Enterobacter species are the third most common cause of nosocomial gram-negative bacillary respiratory infections; as with other aerobic gram-negative rods, risk factors include severity of illness, mechanical ventilation, and prior antibiotic exposure (8). Distinguishing colonization from infection is extremely difficult unless the patient has the same strain of Enterobacter isolated from respiratory secretions and bloodstream or pleural fluid. No data exists to guide therapy for respiratory Enterobacter infections, other than the general guidelines outlined in the discussion of the bacteremia study (7). 


For bacteremia, the drug of choice for Enterobacter is probably a carbapenem if in vitro susceptibility results are not available. Stepdown to cefepime is reasonable once susceptibility results are confirmed.  


Enterobacter is an uncommon cause of meningitis, with two exceptions: postneurosurgical meningitis and neonatal meningitis. The agents with the best activity against Enterobacter and the best CSF penetration are the carbapenems and fourth generation cephalosporins. Members of both classes have shown success in treating gram-negative meningitis (47,50). Until further clinical data is available, meropenem may be the preferred agent; it has a superior safety profile when compared to imipenem in treating central nervous system infections. A review of trimethoprim-sulfamethoxazole (TMP-SMX) therapy for Enterobacter meningitis yielded excellent results (60). In this retrospective study, 13 patients with Enterobacter meningitis complicating trauma or neurosurgical procedures were treated with TMP-SMX with or without other agents (extended-spectrum cephalosporins, aminoglycosides, chloramphenicol) and all were cured.  

Syndromes Associated with Unusual Species of Enterobacter 

Although the vast majority of Enterobacter infections are due to E. cloacaeE. aerogenes and E. agglomerans, occasionally other species occur in discrete syndromes.  


E. sakazakii (formerly yellow-pigmented Enterobacter cloacae) is a sporadic cause of a neonatal meningitis (59). In a review of 15 cases, risk factors for a fatal outcome included prematurity and low birth weight. Overall, about 50% of cases end in death and all survivors experienced severe neurological sequelae. About half of reported cases had cyst or abscess formation. The epidemiology of this organism is poorly understood. E. sakazakii has been isolated from infant formula, but molecular typing techniques have not always confirmed that these strains are the source of disease (39). A recent report described E. sakazakii infections in neonates due to contamination of a blender used in the preparation of formula (4).  

E. cancerogenus (formerly E. taylorae)

E. cancerogenus is an uncommon species which is a sporadic cause of a variety of nosocomial infections (1). This organism has been reported to cause community -acquired infection complicating severe trauma or crush injuries (1). In this report, 5 cases were described among trauma victims. All isolates were obtained from soft tissue and/or blood samples on admission to the hospital, suggesting possible acquisition from soil. All isolates in this report were susceptible to extended-spectrum cephalosporins and quinolones.  

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Alternative Therapies 

Trimethoprim -- Sulfamethoxazole

A small number of series have examined the susceptibility of Enterobacter isolates to TMP-SMX (21,57,59). These reports have found susceptibility rates in excess of 90%. This agent is used infrequently in the treatment of Enterobacterinfections. A report of Enterobacter bacteremia among pediatric patients emphasized the importance of central venous catheters as a portal of entry (63% of cases) and the excellent activity of TMP-SMX (91% susceptible) (2). The utility of TMP-SMX in the therapy ofEnterobacter meningitis is discussed in section IIIB.  


In the ISS survey of 5451 Enterobacter isolates from 396 American ICUs collected between 1990 and 1993, ciprofloxacin was effective against 96% of strains. As previously noted, the prevalence of resistance to quinolones in Enterobacter grew significantly between 1994 and 2000, although 90% of strains remained susceptible in 2000. The newer quinolones such as moxifloxacin and gatifloxacin have greater activity against gram-positive pathogens than the older members of this class, but have no greater activity against gram-negative rods in general and Enterobacter in particular.

It is reasonable to anticipate that quinolone resistance rates will continue to increase over time as these agents are increasingly employed in the treatment of serious Enterobacter infections. A cautionary note is raised by the report of Davin-Regli et al (11). These authors reported an outbreak of Enterobacter hormachei infections among patients in a French hospital who had been treated with quinolones. Twenty-one resistant isolates were detected over a one-year period. All were clonally related by the random amplification of DNA technique.

Quinolone resistance in Enterobacter is usually due to chromosomal genes that may upregulate efflux pumps (42) or confer resistance due to altered DNA gyrase (13). 


As with other bacterial infections, abscesses should be surgically drained in conjunction with appropriate antibiotic therapy. 


There are no vaccines commercially available at this time.  


There are no guidelines specific for Enterobacter infections. However, given the high propensity of this organism to acquire resistance during therapy, it would be prudent to repeat blood cultures at the end of therapy in patients treated for bacteremia.  

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Antibiotic Strategies

Optimizing Pharmacodynamics: One of the potential strategies to improve outcomes in the treatment of gram negative infections in general, and Enterobacter in particular, is to optimize pharmacokinetic and pharmacodynamic properties of antimicrobial regimens. This may lead to better clinical outcomes (54) and less bacterial resistance (30). Thomas and colleagues (54) examined the relationship between antibiotic pharmacokinetics and organism MICs in four clinical trials for nosocomial pneumonia. Phamacodynamic models were developed to identify factors associated with the development of bacterial resistance. Enterobacter species were the second most common pathogen recovered from these patients (after P. aeruginosa). The authors found that combination therapy resulted in much lower rates of emergence of resistance than monotherapy. The authors developed a model in which the ratio of the area under the concentration-time curve from 0 to 24 hours to the MIC (AUC 0-24/MIC) was a significant predictor of emergence of resistance. Ratios under 100 were associated with emergence of resistance.

Kashuba and colleagues (30) analyzed data from 78 patients with nosocomial pneumonia treated with aminoglycosides. AgainEnterobacter was the second most common pathogen recovered from these patients, after P. aeruginosa. The authors found that optimizing aminoglycoside dosing predicted better clinical outcomes. Specifically, the first measured maximum concentration of drug in serum (Cmax)/MIC predicted rapidity of defervescence and leukocytosis.

Computer Assisted Programs and Other Educational Interventions

Workers at the LDS Hospital in Salt Lake City, Utah, have been developing computerized clinical-decision-support programs to assist clinicians treating infectious diseases for many years (17). These tools are intended to improve the use of antiinfective drugs for surgical prophylaxis as well as empiric and directed therapy. The program is linked to the information center of the medical center to maximize the amount of patient-specific information provided to clinicians.  

When gram-negative bacilli are isolated from blood, the program provides a recommendation for empiric therapy based on recommendations from infectious disease physicians. As microbiology data becomes available, it is incorporated into the logic and recommendations are refined. Patient data is used to generate specific drug and dosing recommendations. Alerts are provided for susceptibility mismatches as well as allergies and dosing errors.  

This approach has been shown to diminish the number of adverse drug events, amount of unnecessary therapy, and costs of antimicrobial agents.

This program was developed over many years and is not yet commercially available. The use of infectious disease consultants and antibiotic guidelines have been shown in some cases to diminish antibiotic utilization and the incidence of multiply resistant pathogens (33).  

Infection Control 

Scope of the Problem

The two main engines driving resistance in the hospital are selective pressures due to antibiotics and inadequate attention to infection control measures, especially handwashing. This is a major problem at medical centers worldwide. An illustrative paper is the work of Pittet and colleagues from the University of Geneva, Switzerland (46). Among more than 2000 observed opportunities for handwashing, overall compliance was 48 % and was worse among physicians than nurses. In addition, noncompliance was higher in the ICU, during high-risk procedures, when intensity of care was highest, and on weekends.

Although the use of gloves for all patient contact as part of universal precautions was expected to lead to a significant reduction in cross contamination, the effect appears to be modest (53). In part this is because caregivers may wear the same gloves between patients (44).  

Role of Adequate Staffing

In an intriguing study, Harbarth and colleagues (24) reported an outbreak of Enterobacter cloacae infections in a neonatal ICU which was linked to inadequate staffing. Three epidemic clones were identified. Cross-transmission was facilitated by understaffing and overcrowding. Twenty-five neonates had been housed in a unit built for 15. Observed compliance with handwashing was poor. Termination of the outbreak was accomplished by a decrease in crowding and workload and increased attention to aseptic technique, especially handwashing.  

Role of Newer Handwashing Agents

Several studies document that solutions containing alcohol are superior to conventional handwashing with soap. In a controlled clinical trial at the University of Barcelona, Zaragoza and colleagues (61) compared these 2 techniques head to head in a clinical trial. A total of 47 health care workers were studied. The average reduction in the number of colony-forming units from hand samples was 49.6 % for soap and 88.2 % for the alcoholic solution. Most of the organisms recovered from these samples were staphylococci and enteric bacilli. 10 % of employees complained that the alcoholic solution exacerbated a preexisting skin condition.

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Antibiotic cycling, or rotation, is a strategy of employing different antibiotic classes, usually for a specified time, in an attempt to minimize selective pressure (32). This is commonly done in a defined unit, such as an ICU. The data to support this approach is modest at present but several trials are underway which may shed additional light on its utility.  

The first controlled observations of cycling were studies of aminoglycoside rotation conducted by Gerding and colleagues (23) over a 10 year period at the Minneapolis Veterans Hospital. The motivation to attempt this was provided by a steady rise in the prevalence of gentamicin resistance in gram negative bacilli. Using cycles of 12 to 51 months, these investigators found significantly reduced resistance to gentamicin when amikacin was substituted. More recent work has been conducted by Kollef and colleagues at Washington University in St. Louis, Missouri (31,32). These investigators have shown that inadequate empiric therapy for sepsis in ICU patients is associated with a high mortality rate. In a study of scheduled changes in empiric therapy in an ICU, they looked at a ‘before’ period in which ceftazidime was the preferred agent with an ‘after’ period in which ciprofloxacin was the preferred agent. During the ciprofloxacin period, there were fewer patients receiving inadequate therapy for gram negative infections, especially ventilator-associated pneumonia. Gram negative bacilli resistant to third-generation cephalosporins, particularly P. aeruginosaEnterobacter species, and Stenotrophomonas maltophilia were the major organisms accounting for inadequate therapy (32).  

How much of the improvement in reducing inadequate therapy in these studies can be attributed solely to using a fluoroquinolone (to which resident flora were quite susceptible) instead of a cephalosporin (in a unit with a high resistance rate to these agents), as opposed to cycling per se, remains to be seen. The Centers for Disease Control is sponsoring a multicenter study which is in progress as of the time of this writing, which may shed additional light on the utility of this approach.     

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1. Abbott S, Janda J.M. Enterobacter cancerogenus ("Enterobacter taylorae") Infections associated with severe trauma or crush injuries. Am J Clin Pathol. 1997;107:359-361. [PubMed]

2. Andresen J, Asmar BI, Dajani AS. Increasing Enterobacter bacteremia in pediatric patients. Pediatr Infect Dis J 1994;13:787-92.[PubMed]

3. Archibald L, Phillips L, Monnet D, Mcgowan J, Tenover F, Gaynes R. Antimicrobial resistance in isolates from inpatients and outpatients in the United States: increasing importance of the intensive care unit. Clin Infect Dis 1997;27:211-5. [PubMed]

4. Bar-Oz B, Preminger A, Peleg O, Block C, Arad I. Enterobacter sakazakii infection in the newborn. Acta Paediatr 2001;90(3):356-8.[PubMed]

5. Bellido F, Pechere J, Hancock RE. Novel method for measurement of outer membrane permeability to new beta-lactams in intactEnterobacter cloacae cells. Antimicrobial Agents Chemother 1991:35: 68-72. [PubMed]

6. Bellido F, Pechere J, Hancock RE. Reevaluation of the factors involved in the efficacy of new beta-lactams against Enterobactercloacae. Antimicrob Agents Chemother 1991: 35:73-78. [PubMed]

7. Chow JW, Fine MJ, Shlaes DM, Quinn JP, Hooper DC, Johnson MP, Ramphal R. Wagener MM, Miyashiro DK, Yu VL.Enterobacter bacteremia: Clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med 1991;115:585-590.[PubMed]

8. Chow JW, Yu VL, Shlaes DM. Epidemiologic perspectives on Enterobacter for the infection control professional. Amer J Infect Control 1994;22:195-201. [PubMed]

9. Colardyn F, Faulkner K. Intravenous meropenem versus imipenem/cilastatin in the treatment of serious bacterial infections in hospitalized patients. J. of Antimicrob. Chemotherapy. 1996;38:523-537. [PubMed]

10. Davin-Regli A, Monnet D, Saux P, Bosi C, Charrel R, Barthelemy A, Bollett C. Molecular epidemiology of Enterobacter aerogenesacquisition: one-year prospective study in two intensive care units. J Clin. Micro 1996;4:1474-1480. [PubMed]

11. Davin-Regli A, Bosi C, Charrel R, Ageron E, Papazian L, Grimont P, Cremieux A, Bollet C. A Nosocomial outbreak due toEnterobacter cloacae strains with the E hormaechei genotype in patients treated with flouroquinolones. J Clin. Micro 1997;4:1008-1010.[PubMed]

12. De Champs C, Sirot D, Chanal C, Bonnet R, Sirot J. A 1998 survey of extened-spectrum beta-lactamases in Enterobacteriac France. The French Study Group. Antimicrob Agents Chemother 2000;44:3177-3179. [PubMed]

13. Dekitsch C, Schein R, Markolpulos E, Kuen B, Graninger W, Georgopoulos A. Analysis of mutations to gyrA in quinolone-resistant clinical isolates of E cloacae. J Med Microbiol 1999;48:73-7. [PubMed]

14. Edwards JR. Meropenem: A microbiological overview. J Antimicrob Chemother 1995;36:1-17. [PubMed]

15. Ehrhardt AF, Sanders CC. Beta-lactam resistance amongst Enterobacter species. J Antimicrob Chemother 1993, 32: 1-11.[PubMed]

16. Eisenstein BI, Zaleznik DF. Enterobacteriaceae: in Mandell, Bennet, and Dolin, ed. Principle and Practices of Infectious Diseases, 5th Edition, 2000: Churchill Livingstone. [PubMed]

17. Evans RS, Pestotnik SL, Stanley L, Classen DC, Clemmer TP, Weaver LK, Orme JF, Lloyd JF, Burke JP. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med 1998;338:232-8. [PubMed]

18. Flynn DM, Weinstein RA, Nathan C, Gaston MA, Kabins SA. Patients’ endogenous flora as the source of "nosocomial" Enterobacterin cardiac surgery. J Infect Dis 1987;156:363-68. [PubMed]

19. Fridkin SK. Increasing prevalence of antimicrobial resistance in intensive care units. Critical Care Medicine 2001;29:N64-8. [PubMed]

20. Fridkin SK, Steward CD, Edwards JR, Pryor ER, McGowan JE, Archibald LK, Tenover FC. Surveillance of antimicrobial use and antimicrobial resistance in United hospitals:projects ICARE phase 2. Project Intensive Care Antimicrobial Epidemiology (ICARE) hospitals. Clin Incest Dis 1999;29:245-52. [PubMed]

21. Fung-Tomc J, Dougherty TJ, DeOrio FJ, Simich-Jacobson V, Kessler RE. Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to beta-lactamase levels. Antimicrob Agents Chemother 1989; 33:498-502. [PubMed]

22. Gallagher PG. Enterobacter bacteremia in pediatric patients. Rev Infect Dis 1990;12:808-12. [PubMed]

23. Gerding DN, Larson TA, Hughes RA, et. al. Aminoglycoside resistance and aminoglycoside usage: Ten years of experience in one hospital. Antimicrob Agents Chemother 1991;35:1284-90. [PubMed]

24. Harbarth S, Sudre P, Dharan S, Cadenas M, Pittet D. Outbreak of Enterobacter cloacae related to understaffing, overcrowding, and poor hygiene practices. Infect Control Hosp Epidem 1999;20:598-603. [PubMed]

25. Itokazu GS, Quinn JP, Bell-Dixon C, Kahan FM, Weinstein RA. Antimicrobial resistance rates among aerobic gram-negative bacilli recovered from patients in intensive care units: Evaluation of a national postmarketing surveillance program. Clin Infect Dis 1996;23:779-84.[PubMed]

26. Jacobs C. Life in the balance: cell walls and antibiotic resistance. Science 1997;278(5344):1731-2. [PubMed]

27. Jacobson KL, Cohen SH, Inciardi JF, King JH, Lippert WE, Iglesias T, VanCouwenberghe CJ. The relationship between antecedent antibiotic use and resistance to extended-spectrum cephalosporins in group I beta-lactamase-producing organisms. Clin Infect Dis 1995;21:1107-13. [PubMed]

28. Jacoby GA, Medeiros AA. More extended-spectrum beta-lactamases. Antimicrob Agents Chemother 1991;35:1697-1704. [PubMed]

29. Jones RN. Resistance patterns among nosocomial pathogens: trends over the past few years.  Chest 2001;119:397S-404S. [PubMed]

30. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS. Optimizing aminoglycoside therapy for nosocomial pnuemonia caused by gram-negative bacteria. Antimicr Agent Chemother 1999;43:623-9. [PubMed]

31. Kollef MH. Is there a role for antibiotic cycling in the intensive care unit? Crit Care Med 2001;29:N135-142. [PubMed]

32. Kollef MH, Ward S, Sherman G, Prentice D, Schaiff R, Huey W, Fraser VJ. Inadequate treatment of nosocomial infections is associated with certain empiric antibiotic choices. Crit Care Med 2000;28:4356-64. [PubMed]

33. Lemmen SW, Hafner H, Kotterik S, et. al. Influence of an infectious disease service on antibiotic prescription behavior and selection of multiresistant pathogens. Infection 2000;28:384-7. [PubMed]

34. Livermore DM. Mechanisms of resistance to beta-lactam antibiotics. Scand J Infect Dis 1991;78:7. [PubMed]

35. Livermore DM, Oakton KJ, Carter MW, Warner M. Activity of Ertapenem (MK-0826) versus Enterobacteriaceae with potent lactamases. Antimicrob Agents Chemother 2001;45:2831-7. [PubMed]

36. Maki DG, Rhame FS, Mackel DC, Bennett JV. Nationwide epidemic of septicemia caused by contaminated intravenous products. Amer J Med 1976;60:471-485. [PubMed]

37. Martinez-Beltran J, Canton R, Linares J, Garcia de Lomas J, Gimeno C, Tubau F, Baquero F. Multicentre comparative study on the antibacterial activity of FK-037, a new parental cephalosporin. Eur J Clin Microbiol Infect Dis 1995;14:244-252. [PubMed]

38. Mayhall CG, Lamb VA, Gayle WE, Haynes BW. Enterobacter cloacae septicemia in a burn cernter: epidemiology and control of an outbreak. J Infect Dis 1979;139:166-71. [PubMed]

39. Nazarowec-White M, Farber J. E sakazakii: a review. Int J of Food Microbial 1997;34:103-13. [PubMed]

40. Neuhauser M, Itokazu G, Karam G, Weinstein RA, Quinn JP. Increasing resistance to quinolones and ceftazadime among gram-negative isolates from ICU patients. Abstract No. 129 at 2000 IDSA meeting. New Orleans, LA. [PubMed]

41. Neuwirth C, Siebor E, Lopez J, Pechinot A, Kazmierczak A. Outbreak 0f TEM-24 producing Enterobacter aerogenes in an intensive care unit and dissemination of the extended-spectrum beta-lactamase to other members of the family enterobacteriaceae. J. Clin. Microbiol. 1996;1:76-79 [PubMed]

42. Nikaido H. Preventing drug access to targets: cell surface permeability barriers and in bacteria. Semin Cell Dev Biol 2001;12:215-23.[PubMed]

43. Norrby SR. Carbapenems. Med Clinics North America 1995;79:745-59. [PubMed]

44. Patterson JE, Vecchio J, Pantelick EL, et. al. Association of contaminated gloves wih transmission of Acineobacter calcoacetius var.Antiratus in an intensive care unit. Amer J Med, 1991;91:479-483. [PubMed]

45. Pitout JD, Thomson KS, Hanson ND, Ehrhardt AF, Coudron P, Sanders CC. Plasmid-mediated resistance to expanded-spectrum cephalosporins Enterobacter aerogenes strains. Antimicrob Agents Chemother 1998;42:596-600. [PubMed]

46. Pittet D, Mourouga P, Perneger TV. Compliance with handwashing in a teaching hospital. Ann Intern Med 1999;130:126-130.[PubMed]

47. Rousseau JM, Soullie B, Villevielle T, Koeck JL. Efficiency of cefepime in postoperative meningitis attributable to Enterobacteraerogenes. J Trauma 2001;50:971. [PubMed]

48. Sanders CC. Beta-lactamases of gram-negative bacteria: New challenges for new drugs. Clin Infect Dis 1992;14:1089-99. [PubMed]

49. Sanders WE, Tenney JH, Kessler RE. Efficacy of cefepime in the treatment of infections due to multiply resistant Enterobacter species. Clin Infect Dis 1996;23:454-61. [PubMed]

50. Segal-Maurer S, Mariano N, Qavi A, Urban C, Rahal JJ. Successful treatment of ceftazidime-resistant Klebsiella pneumoniaeintravenous meropenem and intraventricular polymyxin B: case report. Clin Infect Dis 1999;28:1134-8. [PubMed]

51. Segreti J, Levin S. Bacteriologic and clinical applications of a new extended-spectrum parental cephalosporin. Amer J Med 1996;100:45S.1991;35:976-82. [PubMed]

52. Simmons BP, Gelfand MS, Haas M, Metts L, Ferguson J. Enterobacter sakazkii infections in neonates associated with intrinic contamination of a powdered infant formula. Infect Control Hosp Epidemiol 1989;10:398-401. [PubMed]

53. Slaughter S, Hayden MK, Nathan C, Hu TC, Rice T, Van Voorhis J, Matushek M, Weinstein RA. A comparison of the effect of universal use of gloves and gowns with that of gloves alone on acquisition of vancomycin-resistant enterococci in a medical unit. Ann Intern Med 1997;126:1000-1. [PubMed]

54. Thomas JK, Forrest A, Bhavnani SM, Hyatt JM, Cheng A, Ballow CH, Schentag JJ. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob Agent Chemother 1998;42:521-7.[PubMed]

55. Tzelepi E, Giakkoupi P, Sofianou D, Kemeroglou A, Tsakris A. Detection of extended-spectrum beta-lactamases in clinical isolates ofEnterobacter cloacae and Enterobacter aerogenes. J Clin Microbiol 2000;38:542-6. [PubMed]

56. Verschraegen G, Claeys G, Delanghe M, Pattyn P. Serotyping and phage typing to identify Enterobacter cloacae contaminating total parental nutrition. Eur J Clin Microbiol Infect Dis 1988;7:306-7. [PubMed]

57. Wang CC, Chu ML, Ho LJ, Hwang RC. Analysis of plasmid pattern in paediatric intensive care unit outbreaks of nosocomial infection due to Enterobacter cloacae. J Hosp Infect 1991;19:33-40. [PubMed]

58. Watanakunakorn C, Weber J. Enterobacter bacteremia: a review of 58 episodes. Scand J Infect Dis 1989;21:1-8. [PubMed]

59. Willis J, Robinson J. Enterobacter sakazakii meningitis in neonates. Pediatr Infect Dis J. 1988;3:197-199. [PubMed]

60. Wolff MA, Young CL, Ramphal R. Antibiotic therapy for Enterobacter meningitis: A retrospective review of 13 episodes and review of the literature. Clin Infect Dis 1993;16:772-7. [PubMed]

61. Zaragoza M, Salles M, Gomez J, Bayas J, Trilla A. Handwashing with soap or alcoholic solutions? A randomized clinical trial of its effectiveness. Amer J Infect Control 1999;27:258-261. [PubMed]

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Table 1. Antimicrobial Susceptibility Rates (%) for the Four Most Common Species of Gram-Negative Bacilli, 1994-2000

  AA.      E    A. Escherichia coli (n=4027) Klebsiella pneumoniae (n=4877) BEnterobacter species (n=4999)    Pseudomonas aeruginosa (n=8244)
Amikacin 100 94 98 90
Tobramycin 96 85 92 87
Gentamicin 95 85 92 68
Piperacillin 64 39 60 74
Piperacillin/tazobactam 95 87 73 78
Cefepime 98 90 84 71
Ceftazidime 97 87 63 80
Imipenem 100 99 99 83
Ciprofloxacin 97 88 90 76

Table 2   Rates of Cross-Resistance (%) Among Selected Gram-Negative Bacilli, 1994-2000

C. Pseudomonas aeruginosa (Ciprofloxacin)
D. Enterobacter species (Ciprofloxacin)
E. Klebsiellapneumoniae(Ciprofloxacin)
Antimicrobial          % resistant (n=1946)             % susceptible     (n=6298)           % resistant    (n=486)    % susceptible (n=4513)        % resistant (n=603)         % susceptible (n=4274)
Gentamicin 66.0 21.7 48.8 3.9 67.3 7.1
Ceftazidime 39.8 14.0 81.5 31.8 65.2 6.1
Imipenem 37.6 10.9 3.9 1.0 3.2 0.5
Amikacin 26.0 5.6 10.9 0.8 32.6 1.8

 Note:  numbers are percentages

Table 3. Association of Previously Administered Antibiotics with Multiresistant Enterobacter in the Initial Blood Culture

   Multiresistant Enterobacter
Antibiotic*            Isolate n/N (%)    PValue
Any Antibiotic
     Yes       36/103 (35%)
     No        1/26 (4)     .002
Third-generation cephalosporin
     Yes       22/32 (69)
      No          14/71 (20)     .001

*Antibiotics received in the 2 weeks before the initial positive blood culture.

  Data from Chow et al (7)

Table 4. Emergence of Resistance during Antibiotic Therapy for Enterobacter Bacteremia

Patient  Antibiotic Used  Emergence ofResistance toDrug MIC* before Therapy (mg/mL) MIC* after Therapy (mg/mL) Duration of Therapy When Resistance Was Seen (days) Source of  Second Positive Culture
1 Cefotaxime  Cefotaxime  <   >32   16   Intraabdominal  abscess
2 Ceftazidime,  tobramycin  Ceftazidime   <   >16  18    Blood 
3 Ceftazidime  Ceftazidime   <2   >16      Blood
4 Cefotaxime, amikacin  Cefotaxime  < 4   >32      Blood 
5 Ceftizoxime   Ceftizoxime    8     32     Blood
6 Cefotaxime,  gentamicin  Cefotaxime    8   32   7  Blood 
7 Piperacillin, tobramycin  Tobramycin   <0.25    8   8  Two Central venous catheters
Patient  Enterobacter spp. Outcome
1  E. cloacae    Survived
2  E. cloacae   Survived
3  E. cloacae   Survived
4  E. aerogenes   Died
5  E. cloacae   Survived
6  E. aerogenes   Survived
7  E. cloacae  Survived


Baron EJ.  Flow Diagram for  Gram Neg   Rods on BAP & MacConkey (NOT for stool isolates)

Bush K, et al.  MiniReview: Updated Functional Classification of β-lactamases.  Antimicrob Agents Chemother 2010;54:969-976.

Pitout JD. Enterobacteriaceae Producing ESBLs in the Community: Are They a Real Threat?  Infect Med 2007;24:57-65.

Raad, I., Hanna, H. and Maki, D. Intravascular Catheter-related Infections: Advances in Diagnosis, Prevention and Management. The LANCET Infectious Diseases 2007; Vol.7, Issue 10, 645-657.



Clinical Manifestations