30 January 2009
Next update: 6 February 2009
A rare case of Lassa fever was confirmed in a traveller, recently arrived in London from Nigeria, by the HPA's Novel and Dangerous Pathogens Laboratory (NDPL), Porton Down, on 23 January.
After initially having been admitted to Homerton University Hospital on 8 January with fever, confusion and diarrhoea (after experiencing fever and malaise during the flight to the United Kingdom (UK) on 6 January), the patient was transferred on the 22nd to the Infectious Diseases Unit (Hospital for Tropical Diseases), University College Hospital, and then to the Royal Free on the 23rd, for appropriate treatment. Tests for a wide range of common infections associated with travel to Africa carried out in London proved negative. An HPA press release was issued on 23 January confirming that there was no risk to the general public resulting from the case. The patient died on 29 January.
An assessment of the risk of infection for hospital staff was conducted by staff from the North East and North Central London Health Protection Unit, the Centre for Infections in Colindale and the NDPL. This took account of the fact that the case had been cared for in three different wards at the Homerton Hospital, before moving into a side room on 16 January. The following categories of healthcare workers were identified as having been potentially exposed: ambulance staff involved in transporting the patient; medical and nursing staff at the three hospitals; domestic staff at the Homerton Hospital; and pathology staff handling specimens in a number of laboratories. Laboratories holding clinical specimens were contacted and asked to safely destroy these or transfer them to the NDPL for further testing or destruction as appropriate.
The flight details were obtained and the airline company confirmed that there were no passengers on the flight who had required medical assistance. The risk to other passengers on the flight was deemed negligible and therefore they were not traced.
In total, 350 healthcare staff were identified as having been potentially directly exposed through contact with the patient or exposure to bodily fluids. Based on reports of other Lassa fever cases managed in European hospitals the likelihood of transmission to healthcare staff was judged to be very low. Members of staff were contacted either directly in person or by telephone and asked about their contact with the patient and then assigned to one of three categories: no risk, for those who had no contact with the patient (category 1); low risk, for those with direct contact with the patient, or a clinical sample, but using appropriate protective equipment (category 2); and high risk, for those with direct skin, percutaneous or mucosal exposure to bodily fluids (category 3).
Staff in category 1 were informed of the absence of risk and given a general factsheet on the disease. Staff at low risk were informed and asked to report to their occupational health department or other designated manager if they developed a fever within 21 days of their contact with the patient. Staff in the third category were informed and have been asked to self-monitor their temperature and report this to the occupational health department on a daily basis.
Carbapenems (imipenem, meropenem, doripenem and ertapenem) are the most potent β-lactam antibiotics, with the broadest spectra and lowest resistance rates. They are the sole β-lactams to be reliably active against the increasing numbers of Escherichia coli and Klebsiella pneumoniae isolates that are cephalosporin resistant through production of AmpC or extended-spectrum β-lactamases (ESBLs) . In the UK, carbapenem resistance has, so far, mostly been confined to strains of Pseudomonas aeruginosa with permeability mutations and to Acinetobacter baumannii clones with OXA-carbapenemases, although there is also a scatter of Enterobacter and Klebsiella spp. isolates with combinations of an ESBL or AmpC enzyme and impermeability . This latter mechanism confers resistance to ertapenem and reduces susceptibility to other carbapenems, often without causing frank resistance. It is troublesome because the impermeability is sometimes selected during therapy , but strains with the mechanism may be relatively unfit, with impermeability restricting nutrition, and have not caused outbreaks; moreover, their resistance cannot transfer.
Outside the UK there is evidence of a slow but insidious accumulation of Enterobacteriaceae with true carbapenemases i.e. β-lactamases able readily to inactivate carbapenems. Many of these are transferable among strains. Problems include the clonal spread of Klebsiella pneumoniae (mostly) with KPC carbapenemases in the USA  and Israel  and the inter-strain spread of plasmids encoding VIM-1 metallo-β-lactamase among K. pneumoniae in Greece . In Turkey there are outbreaks of K. pneumoniae with OXA-48 carbapenemases . These KPC, VIM and OXA carbapenemases belong to different molecular classes and are not related; nevertheless all confer carbapenem resistance and their diversity makes it harder to design antibiotics that overcome the problem.
Up to 31 December 2007, the HPA' s Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL) had received just eight UK Enterobacteriaceae with carbapenemases. These comprised: five with MBLs, one of them imported with a patient initially hospitalized in Greece; two with KPC enzymes; and one K. pneumoniae with OXA-48 enzyme, from a patient previously hospitalized in Turkey. During 2008, ARMRL received 17 more carbapenemase-producing isolates, thus doubling the total for all previous years combined and leading to the issue of a National Resistance Alert on 23 January, 2009.
These 17 carbapenemase producers comprised:
In the opening weeks of 2009 we have had further MBL-producing Enterobacteriaceae from four hospitals in England and these isolates are presently under molecular investigation.
Microbiologists should be suspicious of any Enterobacteriaceae isolate with resistance or reduced susceptibility to carbapenems, except for Proteus and Morganella spp. with borderline resistance to imipenem only (an inherent trait of these genera) and Enterobacter spp., eight with borderline resistance to ertapenem only (usually associated with high level chromosomal β-lactamase expression). Suspect isolates should be sent to ARMRL for further investigation. Based on current experience, most will prove to have resistance contingent on combinations of an ESBL or AmpC β-lactamase together with impermeability but a minority will be confirmed as carbapenemase producers. Where these enzymes are found we urge the need for stringent infection control and the Centre for Infections Laboratory of Healthcare-Associated Infection will be happy to advise on this aspect. It should be stressed that producers can be difficult to recognize. The K. pneumoniae clone with the KPC carbapenemase is typically susceptible only to gentamicin, tigecycline and polymyxins and has clear resistance to all carbapenems, but many other producers have only low-level resistance and variable (though usually considerable) resistance to other agents. Laboratories should be especially alert to carbapenem-resistant isolates from patients with a history of hospitalization in countries where carbapenemase-producing Enterobacteriaceae are prevalent - particularly Greece, Turkey, Israel and the USA, as these have been a repeated source of introduction to the UK.
Treatment presents major challenges and will often demand antibiotic combinations. Polymyxin is usually active in vitro, but of uncertain efficacy in pneumonia, where it may be advantageous to co-administer the nebulised formulation. Tigecycline is often active in vitro, but has low serum levels and unproven efficacy in severe single-pathogen infections. Aminoglycosides retain strain-variable activity whilst aztreonam is active against some, but not all, MBL producers.
1. Livermore DM, Canton R, Gniadkowski M et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother 2007; 59: 165-74.
2. Woodford N, Dallow JW, Hill RL et al. Ertapenem resistance among Klebsiella and Enterobacter submitted in the UK to a reference laboratory. Int J Antimicrob Agents 2007; 29: 456-9.
3. Elliott E, Brink AJ, van Greune J et al. In vivo development of ertapenem resistance in a patient with pneumonia caused by Klebsiella pneumoniae with an extended-spectrum beta-lactamase. Clin Infect Dis 2006; 42: e95-e98.
4. Bratu S, Brooks S, Burney S et al. Detection and spread of Escherichia coli possessing the plasmid-borne carbapenemase KPC-2 in Brooklyn, New York. Clin Infect Dis 2007; 44: 972-5.
5. Marchaim D, Navon-Venezia S, Schwaber MJ et al. Isolation of imipenem-resistant Enterobacter species: emergence of KPC-2 carbapenemase, molecular characterization, epidemiology, and outcomes. Antimicrob Agents Chemother 2008; 52: 1413-8.
6. Psichogiou M, Tassios PT, Avlamis A et al. Ongoing epidemic of blaVIM-1-positive Klebsiella pneumoniae in Athens, Greece: a prospective survey. J Antimicrob Chemother 2008; 61: 59-63.
7. Carrer A, Poirel L, Eraksoy H et al. Spread of OXA-48-positive carbapenem-resistant Klebsiella pneumoniae isolates in Istanbul, Turkey. Antimicrob Agents Chemother 2008; 52: 2950-4.
8. Livermore DM, Hope R, Brick G et al. Non-susceptibility trends among Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria from bacteraemias in the UK and Ireland, 2001-06. J Antimicrob Chemother 2008; 62 Suppl 2: ii55-ii63.
Applications have been invited for 20 two-year fellowship posts, commencing in September 2009, within the European Programme for Intervention Epidemiology (EPIET) programme . The EPIET programme, managed by the European Centre for Disease Prevention and Control, is aimed at medical practitioners, public-health nurses, microbiologists, veterinarians and other health professionals with experience in public health and a keen interest in epidemiology. The programme provides training and practical experience in intervention epidemiology at national and sub-national centres for surveillance and control of communicable diseases in the European Union. Closing date for submission of applications is 15 February 2009.
1. Further details on the ECDC website at: http://ecdc.europa.eu/en/Job_opportunities/Vacancies/