Gram negative bacteria – Enterobacteriacea

What are the key principles of preventing gram negative bacteria – Enterobacteriacea?

Enterobacteriaceae (e.g., E. coli, Klebsiella sp, Enterobacter sp, Citrobacter sp., Proteus sp., etc) include a large number of gram negative bacilli that are normal colonizers of the human gastrointestinal tract. Other reservoirs include water, plants, soil, and gastrointestinal tract of other animals. Enterobacteriaceae are the most commonly isolated bacteria from clinical specimens (combining inpatient and outpatient specimens) and comprise 21% of all nosocomial isolates in the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) surveillance system in 2006-2007. The two most common organisms, Escherichia coli and Klebsiella pneumoniae, account for 15% of all health care infections.

Specifically, this family accounts for 12.4% of catheter-line associated blood stream infections and 12% of all blood stream infections, 34% of all nosocomial urinary tract infections, 18% of surgical site infections, and 23% of ventilator-associated pneumonias.

There is increasing resistance of these enterobacteriaceae to antibiotics, with endemic rates of organisms resistant to quinolones; third and fourth generation cephalosporins due to endemicity of extended spectrum beta-lactamases (ESBLs) and plasmid mediated amp-C type enzymes; and more recently, the resistance to carbapenem antibiotics via the two most common mechanisms – Klebsiella Pneumoniae Carbapenemase (KPC), and New Delhi Metallobetalactamase-1 (NDM-1), which cause resistance to the broadest of all beta-lactam antibiotics. These carbapenem resistant organisms also contain multidrug resistant genetic elements that code for resistance to most other antibiotics.

Only few antimicrobial agents like colistin, tigecycline, and certain aminoglycosides have consistent in-vitro activity against these carbapenem resistant enterobacteriaceae (CRE), with rising reports of organisms resistant to all available antibiotics. CRE are associated with high morbidity and mortality, with few if any antibiotic treatment options currently and in the near future. CRE have demonstrated epidemic potential, spreading rapidly within individual healthcare settings, and across large geographical areas, and are now endemic across the East Coast United States, Israel, Greece, and India/Pakistan.

With few treatment options for patients infected with CRE, infection control to limit spread of these organisms is critical. However, the best methods to prevent spread are complex, and multi-faceted; and scientific data are still being generated. Nevertheless, the most important goal is early detection within a facility or region, and aggressive containment to limit spread of CRE while incidence is low.

The best infection control practices will include use of sensitive detection methods within the microbiology laboratory, rapid communication of the presence and importance of CRE organisms from microbiology to infection control, aggressive hand-washing, contact precautions and cohorting, antibiotic stewardship, monitoring of admissions of patients from high risk environments (nursing homes, long term care facilities, intensive care units, travel history), use of active surveillance to identify colonization, and communication between public health, and other health care facilities.

What are the conclusions of clinical trials and meta-analyses regarding control of gram negative bacteria – Enterobacteriacea?

The majority of studies are in the setting of a common source or person to person outbreak. As a result, the studies are usually retrospective in design; interventions to control enterobactericeae include multiple interventions simultaneously, making it difficult to assess the relative importance of one aspect of infection control over another.

However, key conclusions in an outbreak situation, in particular of CRE, include:

• All acute care facilities to establish protocol, in conjuction with Clinical and Laboratory Standards Institute (CLSI) to detect and immediately alert infection control members if identification of enterobacteriaceae non-susceptible (intermediate or resistant) carbapenems

• Hand washing of health care workers between patients cannot be overemphasized

• Contact precautions, especially gloving

• Single room if possible; if not, cohort patients.

• Consider dedicated staff to care of CRE patients

• Ensure proper care of invasive monitoring equipment; remove all invasive devices as soon as feasible, and as aseptically as possible

• Optimize environmental cleaning and room disinfection

• Limit use of broad-spectrum antibiotics as part of an antibiotic stewardship program

• Use of initial point prevalence survey (active surveillance cultures of rectum/perirectum) to look for carbapenem resistant or non-susceptible enterobactericeae (CRE) colonization in high risk units, or if cases of CRE are identified within a facility

• Weekly point prevalence surveys until no new cases identified within facility

• Monitor rates of multidrug resistant enterobactericeae imported from outside hospitals, nursing homes, or long term acute care hospitals in order to identify transfer patients who are at highest risk for colonization with these organisms

• Communication and cooperation with other health care facilities and public health departments to notify admission and transfer of patients with carbapenem resistant enterobacteriaceae (CRE)

What are the consequences of ignoring infection control practices related to gram negative bacteria – Enterobacteriacea?

The consequences of ignoring infection control practices related to gram negative enterobacteriaceae are dire. Infections with multi-drug resistant enterobacteriaceae, in particular carbapenem resistant enterobacteriaceae (CRE), are associated with high case fatality rates, as high as 58.8% fatality rate for patients in the ICU and 70-80% fatality rate among patients with bacteremia .

In addition, the plasmid-mediated Klebsiella pneumoniae carbapenemase (KPC) gene has been documented to spread rapidly in an institution(s), from one strain to another, and from one species to another, and can spread across a large geographical region, partially due to the emergence and clonal expansion of a dominant strain of KPC-producing Klebsiella pneumoniae designated multi-locus sequence type 258 (ST 258). Among patients who survive infection or remain colonized but asymptomatic from KPC-producing enterobacteriaceae, these patients are likely vectors of dissemination of these organisms to other patients in health care facilities and community.

Therefore, as treatment options are extremely limited and mortality unacceptably high, prevention, early detection, and early aggressive control are crucial.

Summary of current controversies.

1. Topical application of chlorhexadine: Use of chlorhexadine (topical antiseptic) is now being frequently used in a variety of settings- for hand washing, preoperative skin preparation, oral wash for gingivitis, and for bathing of skin. Its use has been shown to decrease rates of blood stream infections by gram positive organisms, and decrease rates of ventilator associated pneumonia in patients who underwent cardiac surgery. Recent outbreak investigations have used chlorhexadine baths as a part of their multifaceted infection control practices. However, evidence as of yet does not support routine use of chlorhexadine baths or oral solution to decrease rates of infection due to enterobacteriaceae.

2. Selective decontamination of the digestive tract: by orally administering non-absorbable antimicrobial agents has as its aim to prevent or eliminate gut colonization with pathogenic gram negative bacteria, with the goal to decrease rates of infections and mortality. The largest randomized study in ventilated patients in the ICU did show statistically significant decreases in ventilator associated pneumonias and mortality, with transient declines in colonization with multidrug resistant enterobacteriaceae during the 6-month period. However, once the study had concluded, the same units demonstrated rapid rise in multidrug resistant gram negative bacteria. Other studies have showed that in areas of high prevalence of MRSA and VRE, selective decontamination increases rates of infection and colonization with gram positive organisms. Therefore, widespread use of selective decontamination cannot be justified at his time. However, it may have a role to help limit an outbreak due to multidrug resistant enterobacteriaceae, including CRE, though data remains limited.

What is the impact of gram negative bacteria – Enterobacteriacea infections and the need for control relative to infections at other sites or from other specific pathogens?

Enterobacteriaceae are the most frequently isolated group of bacteria when outpatient and inpatient clinical specimens are combined. The family also accounts for 21% of all pathogens isolated in 2006-2007 NHSN surveillance system, which has steadily declined from 42% in 1980-1982, primarily driven by decreased rates of E. coli.

Conversely, gram positive organisms, such as Staphylococci and enterococcal species, have become more predominant causes of nosocomial infection since the early 1980’s.

However, despite the lower prevalence of nosocomial infections due to enterobacteriaceae, because of alarming rates of widespread antibiotic resistance, especially to the broadest antibiotics (carbapenems), infection control of these carbapenem resistant enterobacteriaceae (CRE) is of extreme importance. Case reports have been known to document outbreaks of enterobacteriaceae that are resistant to all known antibiotics (including aminoglycosides, colisitin, and tigecycline), raising true concerns for a new pre-antibiotic era.

Overview of clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and gram negative bacteria – Enterobacteriacea.

See Table I for a summary of infection control stategies.