1. Executive summary
2. Lay summary
4. Guideline Development Team
4.1 Guideline Advisory Group
- •Martin Kiernan, Nurse Consultant, Prevention and Control of Infection, Southport and Ormskirk NHS Trust, Southport, UK
- •Phil Wiffen, Cochrane Pain, Palliative and Supportive Care Group Pain Research, Churchill Hospital Oxford, Nuffield Department of Clinical Neurosciences, Oxford, UK
- •Karla Soares-Wieser, Enhance Reviews Ltd, Wantage, UK
4.3 Source of funding
4.4 Disclosure of potential conflict of interest
- •APRW: Consultant on Drug Safety Monitoring Boards for Roche and Genentech. Advisory panel for 3M.
- •DML: Advisory boards or consultancy for Achaogen, Adenium, Alere, Allecra, AstraZeneca, Basilea, Bayer, BioVersys, Cubist, Curetis, Cycle, Discuva, Forest, GSK, Longitude, Meiji, Pfizer, Roche, Shionogi, Tetraphase, VenatoRx and Wockhardt. Paid lectures for AOP Orphan, AstraZeneca, Bruker, Curetis, Merck, Pfizer and Leo. Relevant shareholdings in Dechra, GSK, Merck, Perkin Elmer and Pfizer (collectively amounting to <10% of portfolio value).
- •JAO: Part-time employment at Bioquell during the production of these guidelines. Paid lectures for 3M. Research funding from Pfizer and the Guy's and St Thomas' Charity.
- •PJ: Advisory board for Baxter.
- •DAE: ECCMID conference attendance funded by Astellas and Eumedica.
- •BO: Advisory board for Astellas and Forest. Lecture for Alere.
- •CM: Travel expenses funded by Mérieux Diagnostics.
- •MC: IPS conference attendance funded by corporate sponsorship from Mölnlycke Healthcare.
- •PH: Consultancy for bioMérieux, Becton-Dickinson, Eumedica, Merck, Novartis, MagusCommunications, Pfizer and Wyeth. Director of ModusMedica (medical education company). Research funded by Merck, Novartis and Pfizer.
- •All other authors declared no conflict of interest.
4.5 Relationship of authors with sponsors
4.6 Responsibility for guidelines
5. Working Party Report
5.1 What is the Working Party Report?
5.2 Why do we need a Working Party Report for these infections?
5.3 What is the purpose of the Working Party Report's recommendations?
5.4 What is the scope of the guidelines?
5.5 What is the evidence for these guidelines?
5.6 Who developed these guidelines?
5.7 Who are these guidelines for?
5.8 How are the guidelines structured?
5.9 How frequently are the guidelines reviewed and updated?
6. Summary of guidelines
- 1,2.The minimum susceptibility tests performed on all significant Gram-negative isolates should include meropenem; in addition, cefpodoxime should be tested for Enterobacteriaceae, and ceftazidime should be tested for Pseudomonas spp.Strong
- 3.Travel history (i.e. countries or known endemic areas visited within previous year) should be collected for all patients with carbapenemase-producing Gram-negative bacteria.Strong
- 4.Each healthcare organization should have access to robust microbiological arrangements for detecting and reporting all MDR Gram-negative organisms in routine clinical samples and for screening using highly-sensitive tests with a diagnostic turnaround time of <48h.Conditional
- 5.Active screening rather than passive surveillance is recommended for high-risk specialties.Conditional
- 6.Patients at high risk of colonization or infection with carbapenem-resistant organisms include those admitted to intensive care units (ICUs) and from long-term care facilities (e.g. care homes).Conditional
- 7.Screening for rectal and wound carriage of carbapenemase-producing Enterobacteriaceae should be undertaken in patients at risk.Strong
- 8.All patients transferred from, or with a history of admission to, healthcare facilities with known endemic carbapenemase-producing Enterobacteriaceae in the preceding year should be screened.Strong
- 9.Screening for carbapenem-resistant Acinetobacter baumannii and MDR Pseudomonas aeruginosa is required in the management of outbreaks.Strong
- 10.A rectal swab (with visible material) or stool sample (and urine sample if catheter present) should be used for screening for MDR Enterobacteriaceae and P. aeruginosa. For Acinetobacter spp., skin sites should be sampled, or, if a catheter or endotracheal tube is present, urine or respiratory secretions should be sampled.Conditional
- 11.In the event of secondary cases of carbapenem-resistant Enterobacteriaceae, standard infection control precautions (SICPs) and contact precautions should be monitored and re-inforced among clinical staff. Screening of patients not identified as carriers should be repeated weekly and on discharge from affected units until no new cases are identified for more than seven days.Strong
- 12.Patients with previous samples with carbapenem-resistant or other MDR Gram-negative bacteria should be screened at the time of admission.Conditional
6.3 Prevention of transmission
- 13.In addition to SICPs, apply contact precautions for those patients who present an infection risk.Strong
- 14.Where possible, single-room isolation should be provided for patients with MDR Gram-negative bacterial infection/colonization, and contact precautions should be continued for the duration of their stay.Conditional
- 15.Use disposable gloves and gowns or aprons to care for patients with MDR Gram-negative bacteria: A. baumannii, carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, P. aeruginosa.Strong
- 16.Identify and place infected and colonized patients in single rooms where available in this order of priority: carbapenem-resistant Enterobacteriaceae, carbapenem-resistant A. baumannii, ESBL-producing Klebsiella spp., carbapenemase-producing P. aeruginosa, ESBL-producing Escherichia coli and other Enterobacteriaceae, AmpC Enterobacteriaceae.Strong
- 17.If insufficient rooms are available, cohort patients following local risk assessment.Conditional
- 18.Hand hygiene is required before and after direct patient contact; after contact with body fluids, mucous membranes and non-intact skin; after contact with the immediate patient environment; and immediately after the removal of gloves.Strong
6.4 Cleaning and environment
- 19.Environmental screening should be considered where there is unexplained transmission of MDR Gram-negative organisms or a possible common source for an outbreak.Strong
- 20.Respiratory and other contaminated equipment should be decontaminated (or respiratory secretions discarded) away from the immediate bed area in designated cleaning sinks and not in handwash sinks.Strong
- 21.For P. aeruginosa, including MDR strains, at a minimum, in accordance with the organization's water safety plan, a risk assessment should be made when levels of patient colonization or infection rise in order to determine if point-of-use filters should be installed or if taps need to be changed.Strong
- 22.Terminal disinfection of vacated areas with hypochlorite should be used in the control of outbreaks of infection due to MDR Gram-negative bacteria.Conditional
- 23.Hydrogen peroxide vapour should be considered as an adjunctive measure following cleaning of vacated isolation rooms/areas.Conditional
- 24.The routine use of selective decontamination of the mouth or digestive tract is not recommended for control of MDR Gram-negative bacteria.Conditional
- 25.Monitor hand hygiene of all staff when patient cohorting is being applied.Strong
7. Implementation of these guidelines
7.1 How can the guidelines be used to improve clinical effectiveness?
7.2 How much will implementation of the guidelines cost?
7.3 Summary of audit measures
- •All Gram-negative isolates requiring antibiotic treatment are to be tested for susceptibility to meropenem (or all blood isolates should be tested).
- •The microbiology laboratory reports all patients infected or colonized with carbapenemase-producing Gram-negative bacteria to Public Health England (PHE) or an equivalent body.
- •All patients colonized or infected with carbapenem-resistant Enterobacteriaceae and A. baumannii are placed under contact precautions within 6h of identification.
- •All patients colonized or infected with carbapenem-resistant Enterobacteriaceae and A. baumannii are placed under contact precautions in a single room or cohort for the duration of their stay.
- •Travel history is obtained at the time of admission for all acute hospital patients, and patients from endemic areas are screened.
7.4 E-learning tools
8.1 Evidence appraisal
|1++||High-quality meta-analyses, systematic reviews of RCTs or RCTs with a very low risk of bias.|
|1 +||Well-conducted meta-analyses, systematic reviews or RCTs with a low risk of bias.|
|1 −||Meta-analyses, systematic reviews or RCTs with a high risk of bias.|
|2++||High-quality systematic reviews of case–control or cohort studies.|
High-quality case–control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal.
Interrupted time series with a control group: (i) there is a clearly defined point in time when the intervention occurred; and (ii) at least three data points before and three data points after the intervention.
|2+||Well-conducted case–control or cohort studies with a low risk of confounding or bias, and a moderate probability that the relationship is causal.|
Controlled before–after studies with two or more intervention and control sites.
|2−||Case–control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal.|
Interrupted time series without a parallel control group: (i) there is a clearly defined point in time when the intervention occurred; and (ii) at least three data points before and three data points after the intervention.
Controlled before–after studies with one intervention and one control site.
|3||Non-analytic studies (e.g. uncontrolled before–after studies, case reports, case series).|
|4||Expert opinion. Legislation.|
|Undesirable consequences clearly outweigh|
|Strong recommendation against|
|Undesirable consequences probably outweigh|
|Conditional recommendation against|
|Balance between desirable and undesirable|
consequences is closely balanced or uncertain
|Recommendation for research and possibly|
conditional recommendation for use restricted to trials
|Desirable consequences probably outweigh|
|Conditional recommendation for|
|Desirable consequences clearly outweigh|
|Strong recommendation for|
8.2 Consultation process
9. Rationale for recommendations
9.1.1 What is the definition of multi-drug-resistant Gram-negative bacteria?
9.1.2 Which Gram-negative bacteria cause infection control problems?
9.1.3 What are the relative contributions of community and hospital acquisition?
9.1.4 What is the evidence for reservoirs and spread of multi-drug-resistant Gram-negative bacteria in care homes and secondary care?
126.96.36.199 High-risk clones
- •The majority of fluoroquinolone-resistant ESBL-producing E. coli causing infection in hospitals and the community belong to sequence type (ST) 131-B2-O25b.20,21
- •The growing prevalence of K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae in hospitals (e.g. in Israel, Italy and the USA) substantially reflects the clonal expansion of ST258 variants with KPC-2 or -3 enzymes.
- •In Russia, Belarus and Kazakhstan, there is extensive nosocomial spread of ST235 P. aeruginosa, with VIM-2 carbapenemase only susceptible to colistin.23
188.8.131.52 Plasmid outbreaks
184.108.40.206 Outbreaks due to Pseudomonas aeruginosa contamination of water systems
220.127.116.11 Long-term care facilities and the spread of multi-drug-resistant Enterobacteriaceae
- Prabaker K.
- Lin M.Y.
- McNally M.
- et al.
Transfer from high-acuity long-term care facilities is associated with carriage of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae: a multihospital study.
- •the frequent transfer into long-term care facilities of patients/residents who were initially colonized or infected in hospitals;
- •oro-faecal transfer within long-term care facilities, reflecting breakdowns of personal hygiene in populations with high rates of dementia and incontinence;
- •frequent antibiotic use and its contingent selection pressure on the gut flora; and
- •high rates of urinary tract catheterization.
9.1.5 Multi-drug resistance in the community
9.1.6 What is the role of agricultural use of sewage and antibiotic treatment in veterinary practice in spreading extended-spectrum β-lactamases?
9.1.7 What insights have national Escherichia coli bacteraemia surveillance provided?
9.1.8 Is there evidence for high-/low-risk areas within a healthcare facility?
- Zarb P.
- Coignard B.
- Griskeviciene J.
- et al.
The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use.
9.2 Is there evidence of differences between organisms in respect of transmission, morbidity and mortality?
9.2.1 Resistant Enterobacteriaceae
|Resistant Enterobacteriaceae||MDR non-fermenters|
|AmpC, ESBL||CPE||Acinetobacter baumannii|
From a taxonomic viewpoint, four species are virtually indistinguishable (A. baumannii, Acinetobacter calcoaceticus, genomic species 3 and genomic species 13TU) so are grouped together as ‘A. calcoaceticus–A. baumannii complex’; however, A. baumannii is by far the most important human pathogen in this group. However, as methods commonly used to speciate Acinetobacter spp. in the clinical laboratory are unable to distinguish these species, the relative contribution of each to the burden of human disease is difficult to establish.
|Pseudomonas aeruginosa||Stenotrophomonas maltophilia|
|Microbiology||Fermentative, oxidase-negative, motile or non-motile, facultatively anaerobic, rods||Non-fermentative, oxidase-negative, non-motile, obligate aerobic, coccobacilli||Non-fermentative, oxidase-positive, motile, aerobic, rods|
332motile, oxidase +/−, obligate aerobic, rods
|Reservoirs||Human and animal gastrointestinal tract, water||Respiratory and gastrointestinal tract, dry surfaces|
|Ubiquitous: plants, animals, moist environments|
|Ubiquitous: plants, animals, humans, moist environments|
|Sites of colonization||Gastrointestinal tract||Skin, respiratory and gastrointestinal tract|
|Gastrointestinal tract, moist body sites (throat, nasal mucosa, axillary skin, perineum)||Respiratory and gastrointestinal tract|
|Duration of colonization||Months to more than one year|
|Days to weeks||–||–|
|Clinical manifestation||Urinary tract (e.g. E. coli), pneumonia (e.g. K. pneumoniae and Enterobacter spp.), intra-abdominal infection|
|Ventilator-associated pneumonia, catheter-related bloodstream and urinary tract infections, wound infections|
|Pneumonia, urinary tract, surgical site, bloodstream infections, cystic fibrosis lung, burns|
|Pneumonia, bloodstream infections; less commonly, urinary tract and wound infections|
|Environmental survival||Hours to weeks on dry surfaces;|
117contaminated environment likely to play a minor role in transmission
|Weeks to months on dry surfaces;|
251difficult to remove from surfaces by cleaning and disinfection
|Contaminates moist hospital environments: tap aerators, respiratory therapy equipment||Contaminates moist hospital environments; can form biofilms on surfaces; low biocide susceptibility|
|Transmission routes||Hands (++), contaminated surfaces (+/−)|
|Contaminated surfaces (++), hands (+), air (+/−)|
|Hands (+), contaminated moist surfaces (+), air (+/−), water systems|
|Hands (+), contaminated moist surfaces (+), air (+/−)|
|Antimicrobial resistance – intrinsic||Ampicillin, first- and second-generation cephalosporins.|
344Serratia and Proteeae spp. are intrinsically resistant to polymyxins
|Ampicillin, amoxicillin-clavulanate, cefazolin, cefotaxime, ceftriaxone, ertapenem, trimethoprim, fosfomycin||Some β-lactams and fluoroquinolones, macrolides, tetracyclines, cotrimoxazole||Most agents except cotrimoxazole|
|Antimicrobial resistance – acquired||Penicillins (except temocillin), ESBLs, carbapenems (through mechanisms other than more common acquired carbapenemases), aminoglycosides, sulphonamides, quinolones|
|Most or all β-lactams, carbapenems, polymyxins (rarely) (exact profile depends on particular carbapenemase and any co-produced ESBL)|
|Quinolones, aminoglycosides, β-lactams (including carbapenems), polymyxins, tigecycline|
|Aminoglycosides, β-lactams (including carbapenems), monobactams, fluoroquinolones, polymyxins||Trimethoprim/sulfamethoxazole|
|Common acquired resistance enzymes||AmpC (intrinsic in Enterobacter), ESBLs (TEM, SHV, CTX-M), various aminoglycoside-modifying enzymes||Carbapenemases (KPC, VIM, IMP, NDM)||Various aminoglycoside-modifying enzymes or ribosomal methyltransferase, class-D OXA type carbapenemases|
|Metallo-β-lactamases (VIM and IMP)||sul genes (resistance to sulphonamide)|
|Mortality (bacteraemia)||Moderate/substantial increase in attributable mortality|
|Stark increase in attributable mortality|
|Minimal increase in attributable mortality|
|Moderate/substantial increase in attributable mortality depending on type of infection|
|Minimal increase in attributable mortality|
|Risk factors||Hospital: prolonged hospital stay, prior hospitalization, previous use of antibiotics, presence of indwelling catheters, mechanical ventilation|
Community: older age, recurrent urinary tract infections/prior invasive procedures (e.g. catheterization), known faecal carriage, contact with healthcare facilities, antimicrobial treatment
|Prior antimicrobial use, length of stay, severity of illness, mechanical ventilation, admission to ICU, high procedure score, presence of wounds, positive culture from a blood isolate, transfer between hospital units within the same hospital, prior surgery, prior hospital stay, proximity to other colonized/infected patients, presence of a biliary catheter and recent transplantation.|
168For NDM, prior hospitalization on Indian subcontinent; for OXA-48, prior hospitalization in Middle East
|(i) Major trauma, particularly burns, surgery and battlefield injury; (ii) previous antimicrobial therapy; (iii) prolonged hospital and ICU stay; (iv) mechanical ventilation, drainage tubes and indwelling catheters; (v) high prevalence of MDR Acinetobacter spp. on the unit; (vi) proximity to other colonized/infected patients|
|(i) Prior use of antibiotics; (ii) mechanical ventilation; (iii) prolonged hospital and ICU stay; (iv) co-morbidities (e.g. cystic fibrosis, burns units)|
|Severely compromised health status, malignancy, indwelling devices (such as intravascular catheters and ventilation tubes), exposure to broad-spectrum antimicrobials, long hospital stay, ICU stay|
|At-risk population||Patients in acute, long-term and community settings; patients travelling to areas of high prevalence|
|Patients in acute settings, particularly those with recent travel to areas of high prevalence|
|Immunocompromised patients in the ICU and burns units;|
330rare cause of community-acquired infection
|Immunocompromised patients in the ICU and burns units; patients with cystic fibrosis;|
345rare cause of community-acquired infection
|Immunocompromised patients in the ICU; patients with cancer and cystic fibrosis; rare cause of community-acquired infection|
|Common international clones||E. coli ST131 with CTX-M ESBLs|
|K. pneumoniae ST258 with KPC enzymes|
|International clones I–III|
19A few international high-risk clones [e.g. ST111 (serotype O12)] acquire multi-drug resistance; spread of ST235 with VIM carbapenemase in Russia, Belarus and Kazakhstan
9.2.2 Acinetobacter baumannii
9.2.3 Pseudomonas aeruginosa
9.3.1 Selection of samples and antimicrobials to test
- Woodford N.
- Pike R.
- Meunier D.
- Loy R.
- Hill R.
- Hopkins K.L.
- •The chromogenic oxyimino-cephalosporin HMRZ-86 turns from yellow to red on hydrolysis.149If used in combination with inhibitors, it can be used to distinguish strains with AmpC, ESBLs or metallo-carbapenemases, although KPC enzymes may be confused with AmpC and it is unclear whether OXA-48 is detected.
- •Acidimetric β-lactamase tests can be adapted to detect carbapenemase producers, as in the ‘Carba-NP’ test where, again, some authors report problems in detecting OXA-48.150,151,152
- •MALDI-ToF assays for carbapenemase activity, exploiting the molecular mass change that occurs when the β-lactam molecules are hydrolysed.153
- Cuzon G.
- Naas T.
- Bogaerts P.
- Glupczynski Y.
- Nordmann P.
18.104.22.168 When to seek reference laboratory typing of isolates
- •To inform cross-infection and outbreak investigations.
- •To seek a particular type associated with specific clinical characteristic(s) (e.g. K1 capsular type of CC 23 of K. pneumoniae associated with hypermucoviscosity and liver abscesses).
- •To provide national/international context (e.g. in tracking the spread of ‘high-risk clones’, such as ST258 K. pneumonia, with KPC carbapenemases).
- van Belkum A.
- Tassios P.T.
- Dijkshoorn L.
- et al.
Guidelines for the validation and application of typing methods for use in bacterial epidemiology.
9.3.2 What national surveillance is performed and how should it be developed?
- Magiorakos A.
- Suetens C.
- Monnet D.L.
- Carlo Gagliotti C.
- Heuer O.E.
The rise of carbapenem resistance in Europe: just the tip of the iceberg?.