2.0 Multi-Drug-Resistant Gram-Negative Bacteria (MDRGNB)
Enterobacterales are a large family of Gram-negative bacteria that usually live harmlessly (and without symptoms) in the gut of humans and animals. They include species such as Escherichia coli, Klebsiella spp. and Enterobacter spp. However, these organisms are also some of the most common causes of infections in healthcare, including urinary tract infections, intra-abdominal and bloodstream infections.
Multi-drug-resistant strains of Enterobacterales, and other Gram-negative bacteria (such as Pseudomonas aeruginosa and Acinetobacter baumanii) have been reported in healthcare settings across the world.
These bacteria pose a global threat to public health (Ref) due to the limited options available for treatment of infections, as well as lack of newly developed antimicrobial medications, and infection can carry a higher mortality rate.
Resistance of Gram-negative organisms can be intrinsic (a natural characteristic), or organisms can acquire resistance. This is much more worrying than intrinsic resistance, as it means the bacterium has gained the ability to become resistant to carbapenems. This occurs by the sharing of genes encoding carbapenemase enzymes (usually located on mobile elements such as plasmids) between strains, species, and genera of bacteria.
Risk factors for colonisation, and possible infection, with MDRGNB include:
• Prolonged healthcare contact/ hospital stay, especially in countries with a high prevalence of MDRGNB
• Extended antibiotic therapy, especially with broad-spectrum antibiotics
• Patients with impaired immunity (Critical Care, oncology and neonatal units)
• Gastrointestinal surgery
• Chronic wounds
• Use of urinary catheters and other invasive devices
The most common route of transmission of MRGNB in healthcare is via:
• Hands of healthcare workers following direct contact with an infected or colonised person
• Equipment that has not been appropriately decontaminated following use with an infected or colonised person
• Environmental contamination from healthcare water and drainage systems (including hand washing basins). Refer to the clinical hand wash basin standards described in IPC05: Hand Hygiene policy (section 5.2), and IPC28b: Decontamination and Management of the Care Environment (section 4.0).
2.1 Carbapenemase-Producing Enterobacterales (CPE)
Carbapenems are a valuable family of β (Beta)-lactam antibiotics normally reserved to treat serious life-threatening multidrug-resistant Gram-negative infections in hospitals. They include meropenem, ertapenem and imipenem.
Carbapenemase-Producing Enterobacterales (CPE) are Gram-negative bacteria that produce carbapenemases - enzymes that inactivate carbapenems and other β-lactam antibiotics. CPE are the true super-bugs. Spread of CPE is an increasing threat to public health and medical treatment pathways in the UK. An increase in prevalence of colonisation with CPE, will inevitably lead to an increase in difficult-to-treat infections.
CPE acquired carbapenemases, a particular concern as these genes (usually located on mobile elements such as plasmids) can move vertically (within a strain) and horizontally (between strains, species and genera).
Since October 2020, acquired CPE isolated from human samples are included in the Health Protection (Notification) Regulations 2020 (UKHSA 2022).
2.1.1 Types of CPE – The ‘Big Five’
The five main carbapenemases (all of which have been identified in patients admitted to the Frimley Health over the past five years), are:
OXA (Oxacillin carbapenemases)
NDM (New Delhi metallo-beta-lactamase)
KPC (Klebsiella pneumoniae carbapenemase)
VIM (Verona integron-encoded metallo-beta-lactamase)
IMP (Imipenemase metallo-beta-lactamase)
2.1.2 Screening for CPE
Active screening for CPE is recommended to minimise transmission from patients colonised with CPE, and to guide antimicrobial treatment of CPE infection (UKHSA 2022).
CPE is the only group of MDRGNB that are currently screened for routinely at Frimley Health.
Patients routinely requiring screening on admission to Frimley Health are:
• Patients with known history of CPE
• Patients with known contact with a case of CPE
• Patient transfers from other acute hospitals (including abroad)
• Patients who have had an inpatient admission to another acute hospital (including abroad) in the past 12 months
• Patients requiring the following:
- Renal dialysis
- Critical Care/ ITU admission
- Haematology/ Oncology admission/ chemotherapy treatment
- Vascular surgery
Note: Amendments in CPE screening guidance will be put in place in response to changes in local and regional prevalence, outbreaks, or changes in case epidemiology (patient populations and risk factors).
2.1.3 How to screen for CPE
A CPE screen is taken either by:
• A rectal swab (recommended, as the most sensitive test). A rectal swab is a specimen taken by gently inserting a swab inside the rectum 3-4cms beyond the anal sphincter, rotating gently and removing. Normal saline can be used to moisten the swab prior to insertion. The swab should have visible faecal material to enable organism detection in the laboratory.
• A stool specimen
In addition, patients meeting the criteria for CPE screening who are admitted with wounds or invasive devices, should also have these screened.
Order ‘CPE screen culture’ on EPIC.
Patients with a known history of CPE will remain in isolation for the duration of their admission, regardless of whether their admission screen is positive or negative. Patients who test positive on admission will also be isolated throughout their admission. The patient and their GP will be informed of the result. A Trust CPE Screening leaflet is available for patients.
Patients who test negative on admission (and have no prior history of CPE), should be re-screened again if antibiotic treatment is started during that episode of care (ideally 24 hours after the antibiotics have started).
A CPE Screening & Care Pathway becomes accessible on Epic, following a positive result, to guide the care of patients with CPE.
2.2 Beta-Lactamase-Producing Enterobacterales
Resistance to third-generation cephalosporins is typical of MDRs, being mainly due to the production of extended spectrum β-lactamases or AmpC-type β-lactamases.
2.2.1 Extended Spectrum β-lactamases (ESBL)
Increased use of antibiotics (particularly 3rd generation cephalosporins) has been associated with the emergence of ß-lactamases.
Most ESBL-producing E. coli are resistant to cephalosporins, penicillins, fluoroquinolones, trimethoprim, tetracycline and some other antibiotics, which can leave very limited options for oral treatment in the community.
2.2.2 AmpC β-lactamases
Production of AmpC enzymes can be either inducible (a gene that is ‘turned off’ but can be expressed when needed) or constitutive (genes that are expressed continually), resulting in different resistance phenotypes.
2.3 Gram-Negative Bacteria with Intrinsic Resistance to Carbapenems
Resistance to some or all carbapenems is an intrinsic (natural) characteristic of some Gram-negative bacteria. These groups of organisms can also be called Carbapenem-Resistant Organisms (CRO).
2.3.1 Multi-Drug-Resistant Acinetobacter species
Many hospitals in England have encountered problems with multi-resistant Acinetobacter spp. (particularly carbapenem-resistant Acinetobacter baumanii (CRAB)).
Multi-drug resistant Acinetobacter is defined as:
• An isolate that has been shown to be resistant to any aminoglycoside (e.g. gentamicin) AND
• To any 3rd generation cephalosporin (e.g ceftazidime)
• More resistant strains can be resistant to Imipenem or colistin
2.3.2 Stenotrophomonas maltophilia
This bacterium commonly resides in water, soil and sewage. S. maltophilia is an organism of low virulence and is a frequent coloniser of fluids used in the healthcare setting, such as irrigation solutions and intravenous fluids, and of patient secretions, e.g. respiratory secretions, urine, or wound exudates. S. maltophilia has limited ability to cause infection in humans, and usually must bypass normal host defences to cause infection.
Risk factors for colonisation and infection are similar to those for Acinetobacter.
2.3.3 Multi-Drug-Resistant Pseudomonas species
Multi-drug-resistant Pseudomonas spp. are resistant to at least two of the following: ceftazidime, piperacillin/tazobactam, gentamicin (or other aminoglycoside), ciprofloxacin. They are occasionally resistant of carbapenem antibiotics.
2.3.4 Burkholderia cepacia complex
The Burkholderia cepacia complex (B. cepacia) consists of several species of bacteria that are found in the natural environment. Some of these species threaten the health of people with cystic fibrosis (CF). There are about 17 different B. cepacia complex species.
The ones most often found in people with CF are:
• B. cenocepacia
• B. multivorans
• B. vietnamiensis
• B. dolosa
• B. cepacia
B. cepacia has high intrinsic resistance to antimicrobials and is generally resistant to the antibiotics active against P. aeruginosa. It is resistant to aminoglycosides, colistin, ticarcillin, azlocillin and imipenem.
CF patients appear to be susceptible to lung infection with these organisms, which can be particularly severe and leading to fulminant necrotizing pneumonia in a minority of patients. Patients with chronic granulomatous disease may also succumb to B. cepacia infection due to its resistance to opsonophagocytes of patients with this disease (CDC 2024). Patients with B. cepacia must not be admitted as inpatients to the FPH Cystic Fibrosis Unit and should not attend Outpatient clinics with non-cepacia CF patients.
These bacteria pose very little medical risks to healthy people. However, some people who have a serious illness or immunosuppression may be at risk of an infection from these bacteria.
3.0 Prevention & Control of MDRGNB
3.1 Antimicrobial Stewardship
• Use the Trust Microguide to guide treatment of infection.
• Send appropriate microbiological samples for culture, to aid prompt diagnosis and treatment of infections.
• Please contact the on-call medical microbiologist (via the hospital switchboard) to review antibiotic prescribing for complex case (including all CPE infections).
• Treatment of MDRGNB colonisation is not recommended.
• A cluster of cases should trigger a review of antimicrobial prescribing.
3.2 Patient Placement and Management
• Patients known to be colonised, or have an infection, with a MRGNB (including CPE), will have this flagged on the Epic ‘infection status’.
• Positive patients are advised to be cared for in a single room until discharge. Refer to IPC04: Guidelines for the Isolation of Patients.
• Refer to both IPC28a: Personal Protective Equipment use for Infection Prevention & Control), and the NIPCM (NHSE 2024) guidance on Standard IPC, and Transmission-based, precautions.
• Inform patient of the rationale for isolation. The Frimley Health FT leaflet ‘Multi-Resistant Gram-Negative Bacteria information for patients, relatives and carers’ is available on the Trust intranets site and from PALS.
• If one or more cases of carbapenemase-producing enterobacteriacae occurs in hospital in-patients, the Infection Prevention & Control Team must be contacted to carry out further investigation (along with UKHSA) and for advice on patient management.
• On patient transfer, the receiving ward/ department/ healthcare facility (including GP) should be informed about the patient’s MRGNB-carriage, as with any antimicrobial-resistant micro-organism.
3.6 Environmental Decontamination
• Enhanced cleaning of the patient’s room/ bed space with a combined detergent/ chlorine releasing solution with a concentration of 1000ppm available chlorine, focussing on frequently touched and dust-collecting horizontal surfaces (sinks, beds, tables, ventilators, pillows, sinks, doorknobs, computer keyboards, curtain rails and telephones).
• Refer to IPC28b: Decontamination and Management of the Care Environment.
• Refer also to the NIPCM (NHSE 2024) guidance on safe management of the care environment.
• A deep clean of the room is required on discharge of the patient, including disposal of all un-used disposable items. If pillows are wipe-clean only, they should be disposed on patient discharge.
• Environmental screening must only be on the advice of the Infection Prevention & Control Team.