Aura 2016: first Australian report on antimicrobial use and resistance in human health

6.2 Carbapenemase-producing Enterobacteriaceae and carbapenem resistance

Contributor: Associate Professor Thomas Gottlieb, Clinical Associate Professor Medicine (Immunology & Infectious Diseases), Concord Clinical School

The threat to public health from the spread of multidrug-resistant bacteria has received increasing attention. Measuring the extent of antimicrobial resistance (AMR) is crucial to defining the current and future problem. Of foremost concern is the potential spread of carbapenemase-producing organisms in the community and healthcare facilities.

Carbapenems (including meropenem and imipenem) are the broadest-spectrum antimicrobials available. They are usually reserved for treatment of the most severely ill patients, and those with infections caused by bacteria that are resistant to multiple other antimicrobial classes.

If an organism is resistant to carbapenems, it effectively means that it is resistant to all β-lactam antimicrobials – the key group of antimicrobials in therapeutic use in Australia.

Management of carbapenemase-producing Enterobacteriaceae infections

Colonisation with CPE usually occurs in the patient’s gastrointestinal system. Most patients do not develop any associated illness, but they can spread the resistant bacteria to others. Some patients may develop clinical signs of CPE infection, such as urinary tract or biliary infections.

CPE management in a hospital or long-term care setting depends on effective infection control practices to limit the establishment and spread of the organisms. This requires significant policy development, planning, and physical and human resources to pre-emptively screen for CPE carriage and to isolate at-risk or colonised patients.

Impact and spread of carbapenemases

Some bacteria that are resistant to carbapenems produce an enzyme called a carbapenemase. In gram-negative bacteria (such as Pseudomonas aeruginosa, Acinetobacter baumannii and the Enterobacteriaceae), different groups of acquired genes code for carbapenemases. The main groups of carbapenemases are KPC, VIM, IMP, NDM and OXA.

Carbapenemases are ‘promiscuous’ – that is, the genes encoding these enzymes can be highly transmissible within and between species of bacteria. Carbapenemase genes are found on plasmids or parts of bacterial chromosomes that also encode other bacterial resistance factors, such as those coding for ESBLs, and fluoroquinolone and aminoglycoside resistance. This means that bacteria that have acquired carbapenemases are highly multidrug resistant, leaving very few – if any – antimicrobial options for therapy.

CPE have high epidemic potential. Internationally, the development and spread of CPE are promoted by use – and overuse – of antimicrobials in health care, agriculture and food production. In the long term, reducing the proliferation of known or new carbapenemase enzymes depends on effective regulation of AU internationally, and prescribers’ willingness to conform to antimicrobial treatment guidelines and antimicrobial stewardship.

International spread of carbapenemase-producing Enterobacteriaceae

Data indicates that Enterobacteriaceae with KPC carbapenemases are spreading in the United States, Israel and South America. Greece and Italy have recently reported outbreaks in which 50% of K. pneumoniae bacteraemia isolates were KPC producers. Recent reports from Italy also indicate that KPC-producing K. pneumoniae has become resistant to colistin, following the use of this agent as a last-line antimicrobial in critically ill patients.

The carbapenemase NDM-1 was first recognised on the Indian subcontinent. It has spread widely in both hospitals and the community. Data from 2011 estimates that 100–200 million people could be colonised by Enterobacteriaceae that possess this enzyme. NDM-1 has since been recognised in other parts of Asia, and has spread through international travel, resulting in multiple sporadic cases in Australia.

The OXA-48 enzyme has been documented in north Africa, Turkey and areas of the Middle East, and has also disseminated widely through travel and patient transfer. A large hospital outbreak was documented in Rotterdam, and OXA-48 is the most common CPE identified in French laboratories. An OXA-48-type variant (OXA-181) has been isolated in India, and is often associated with NDM-1.

Carbapenemase-producing organisms in Australia

To date, the rates of reported CPE in Australia have been low. Active surveillance through the Australian Group on Antimicrobial Resistance detected only rare isolates in surveys until 2012. In 2013 and 2014, 14 of 4958 (0.28%) and 14 of 5796 (0.24%) isolates of Enterobacteriaceae from Australian patients with bacteraemia produced carbapenemases.

The 14 isolates in 2014 included the enzyme groups IMP-4 (seven isolates), KPC-2 (three isolates), VIM-1 (two isolates), NDM-4 (one isolate) and OXA-181 (one isolate). All isolates were individual sporadic cases, except for the three cases of KPC-2, which were part of a sustained local hospital outbreak.

Implications for Australia

Carbapenemases are present in Australia at low levels, but seem to be widely disseminated throughout the country. The enzyme group IMP-4 is the most commonly reported CPE in Australia. Molecular analysis of these isolates has found that the gene for the enzyme is located on a range of plasmids in different isolates, suggesting that multiple recombination events have taken place over time. Recently, IMP-4 was identified in a pandemic strain of E. coli ST131 (a high-risk, highly transmissible clone), and also in animal and environmental isolates, suggesting low-level but extensive dissemination of this carbapenemase in Australia. The combination of wide dissemination and genetic recombination means that IMP-4 has a high likelihood of becoming more common and very widespread in the future.

A recent outbreak of a KPC-producing K. pneumoniae in a Victorian hospital led to sustained hospital cases for more than 12 months and secondary cases presenting to other hospitals. The strain was not initially recognised as a CPE. This highlights the need for vigilance, and for up-to-date methods of detection to be in place in all routine microbiology laboratories.

Potential actions

Containment of CPE has become a national priority. The Commission is building a national alert system (CARAlert) for critical AMR, with CPE being the most important of these. The alert system will provide near-immediate information on confirmed CPE around Australia, allowing more coordinated action should an outbreak(s) be identified.

The Commission has produced guidance on the detection and containment of CPE at the individual institution level. This guidance should be reviewed and updated regularly as new information comes to light.

The outbreak of a KPC-producing K. pneumoniae in Victoria has shown that a statewide ‘public health’ approach – that is, an approach that is beyond the single institution – is essential to the containment of CPE, because strains do not remain confined to a single hospital. The Victorian Department of Health and Human Services has recently drafted guidelines for statewide containment. Other states and territories should consider similar actions.