resistance, based on the UN’sintergovernmental panel on climatechange (IPCC). Farrar and Woolhouse2

emphasised that this should beresponsible for finding ways to drasticallyreduce antibiotic use in order to halt thespread of resistance and work withindustry to find new ways to developtreatments to fight infections.2

However, while internationalcollaboration is seen as crucial, ProfessorKevin Kerr, consultant microbiologist atHarrogate District Hospital and chair ofthe European Society for ClinicalMicrobiology and Infectious Diseases’Study Group on Food and WaterborneInfection, stressed: “We [still] have to dowhat we can... individually and collectivelywithout waiting for international efforts toget off the ground. Yes, it’s a huge globalproblem, but we must strike a balancebetween giving the impression that it is anissue so large that only governments canaddress it and the fact that, as clinicians,we can – and should – prescribeantibiotics prudently in our own day-to-day working lives.”

Antibiotic resistance in the UKChief Medical Officer, Professor DameSally Davies, has driven the issue high upthe Government’s agenda, publishing afive-year strategy in September 2013, toslow antimicrobial resistance throughimproved understanding, effectivestewardship of existing treatments anddevelopment of other therapies anddiagnostics. In addition, by the end of2014 antimicrobial resistance is to beplaced on the Cabinet Office’s nationalrisk register, acknowledging the issue as acivilian threat on a par with pandemic flu

While there is a need for international efforts to tackle thethreat posed by antimicrobial resistance, how can clinicians,pharma and governments take positive steps to help avert a crisis? SUSAN PEARSON reports.

The threat from antibiotic resistance is no longer a prediction for the future, it is happening right now, worldwide andcan affect anyone from any country: thisis the verdict of a new World HealthOrganization (WHO) report on antibioticresistance.

The report is the first published by the WHO, to tackle the issue. It aims tokick-start improved collaboration intracking drug resistance globally andbetter-designed targeted solutions.

Issuing a stark warning, Dr KeijiFukuda, WHO assistant director-generalfor Health Security, highlighted the needfor urgent action: “Without urgent,coordinated action by many stakeholders,the world is headed for a post-antibioticera… Unless we take significant actions toprevent infections and also change how weproduce, prescribe and use antibiotics...theimplications will be devastating.”1

In May, a new Antibiotic ResistanceCoalition (ARC), comprising civil societyorganisations and stakeholders frommultiple sectors on six continents andlaunched during the 67th World HealthAssembly, called on the WHO to pass acritical resolution to control the escalatingantimicrobial resistance crisis.

“If the resolution is not passed, and theWHO and its Member States do not actquickly, there will be disastrous globalconsequences,” said Otto Cars, founder ofReAct (Action on Antibiotic Resistance).

Just two days before the World HealthAssembly, Professor Jeremy Farrar, headof the Wellcome Trust, and MarkWoolhouse, professor of infectiousdisease epidemiology at EdinburghUniversity, urged world leaders to set upan international panel on antimicrobial

Antibiotic resistance: a call for urgent action

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and terrorism. All this builds on the earlierTARGET primary care campaign aimed atimproving antimicrobial stewardship andthe November 2011 Start SMART – thenFOCUS campaign for secondary care.

However, although WHO records highlevels of antibiotic resistance to a wide rangeof bacteria, as well as resistance to antivirals,the UK pattern, according to Public HealthEngland (PHE), involves far fewerorganisms. Most concern is focused onresistance to carbapenems, the antibiotics oflast resort for a number of infections.

One of the misconceptions about theproblem, certainly in the UK, is thathospitals are seen as the main breedinggrounds for resistant superbugs. But this isnot the case according to Prof Kerr. “Thereality of my daily working life as a

47

‘Public Health England

has produced a toolkit

to detect, manage and

control infections with

CPE and other antibiotic

resistant bacteria.’

England by PHE rising fromless than five patients in 2006 toover 600 in 2013. Around 120English Trusts have beenaffected in the last five years.

PHE is now tackling thisproblem head-on with a newToolkit to detect, manage andcontrol infections with CPE andother antibiotic-resistantbacteria. Launched in March,the Toolkit provides practicaladvice for clinicians and staff atthe frontline in acute care

settings. It deals with four key elements,providing protocols for: the earlymicrobiological testing of any patientswho are suspected of being colonised orinfected; management of the patient toprevent any resistant bacteria spreading toothers; putting in place strict infectionprevention and control procedures,including hand washing and thoroughcleaning and decontamination; andreviewing the use of medical devices andprescribed antibiotics.

The Toolkit also provides a series ofchecklists for Trust boards, executives andinfection prevention and control teams,materials to assist public health riskassessment, for example case/contactspreadsheets, and further materials toprovide public information.3

Enterobacteriaceae are naturally‘carried’ in the gut and are generallyharmless but may cause serious infectionif spread to other parts of the body, suchas the urinary tract or bloodstream. This

patient’s very severe allergy to penicillin,to which meropenem is related, the onlydrug left was colistin, an antibiotic whichfell out of favour in the 1970s due to itstoxicity to the nervous system andkidneys. In this case the patient waslucky, she responded well to treatmentwithout serious side effects.

CPE toolkit The bacteria currently causing mostconcern in the UK are carbapenemase-producing Enterobacteriaceae, commonlyreferred to as CPE. These are strains ofgut bacteria that have developedresistance to carbapenems, an importantgroup of ‘last resort’ antibiotics. Thetherapeutic options for infections causedby CPE bacteria are very limited.Treatment frequently requires use ofrelatively untested combinations of drugswhich include older antibiotics. There hasbeen a sustained increase in CPE inrecent years, with cases identified in

microbiologist is that I often sign outbetween 20 and 30 reports on veryresistant bacteria every day, notnecessarily for the hospital wards but forGP surgeries and outpatient clinics, too.These organisms are found in allhealthcare settings. The bugs do notrecognise physical or administrativeboundaries. Contrary to what might beexpected, we are more likely to see someresistant bacteria known as ESBLs(Extended-Spectrum Beta-Lactamases),in primary care. But we [also] have toremember that about three-quarters of allantibiotics are prescribed in primary care.”

Describing the situation ‘on theground’, Prof Kerr said: “The focus in thelast few years has been on MRSA but westill have five or six antibiotics we can useto treat these infections. With some ofthese multi-resistant Gram-negativeorganisms, we only have one or twoantibiotics left. In some cases, none atall.” He gives the example of an elderlywoman, a nursing home resident, proneto urinary infections, usually manifestingas straightforward ‘cystitis’. But infectionin this patient can lead her to become veryaggressive towards her carers, whichmeans the infection must be treatedquickly. A urinary specimen from thispatient proved completely resistant to sixfirst line antibiotics and to five of a furthersix, leaving meropenem as an option. Thisis a drug of last resort and can only begiven intravenously; the patient wouldhave to be admitted to hospital – just for acase of cystitis. However, because of the

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THE CLINICAL SERVICES JOURNAL AUGUST 2014

‘With some of these

multi-resistant Gram-

negative organisms,

we only have one

or two antibiotics left.

In some cases, none at all.’

Kevin Kerr.

Prime Minister announces review on AMRThe Prime Minister, David Cameron, has commissioned an independentreview to explore the economic issuessurrounding antimicrobial resistance(AMR). The review will be led by theinternationally renowned economist Jim O’Neill and co-funded and hostedby the world’s second largest medicalresearch foundation, the WellcomeTrust, to explore the economic issuessurrounding antimicrobial resistance.

The review will set out a plan forencouraging and accelerating thediscovery and development of newgenerations of antibiotics, and willexamine:• The development, use and regulatory

environment of antimicrobials,especially antibiotics, and explorehow to make investment in newantibiotics more attractive topharmaceutical companies and otherfunding bodies.

• The balance between effective andsustainable incentives for

on creating a cheap, accurate and easy-to-use test for bacterial infectionsthat will allow doctors and nurses tobetter target antibiotics and preventover-use.

The Prime Minister, David Cameron,said: “If we fail to act, we are looking atan almost unthinkable scenario whereantibiotics no longer work and we arecast back into the dark ages of medicinewhere treatable infections and injurieswill kill once again.

“That simply cannot be allowed tohappened and I want to see a stronger,more coherent global response, withnations, business and the world ofscience working together to up our gamein the field of antibiotics.”

The review will present its initialfindings during 2015 with a final reportand recommendations to then followduring 2016. This process will runalongside – and engage closely with –the WHO’s development of a GlobalAction Plan on AMR.

investment, and the need to conserveantimicrobial drugs so they remaineffective for as long as possible.

• How governments and other funderscan stimulate investment in newantimicrobials and timeframes andmechanisms for implementation.

• Increasing international cooperationand support for action by theinternational community, includingmuch closer working with low andmiddle income countries on this issue.

Jim O’Neill will work independently ofGovernment, and will have full freedom toapproach the issues and the evidence ashe sees fit. He will work with internationalexperts covering all aspects of the AMRpipeline and associated economic issuesto identify a range of proposals that canform the basis of a new, strengthenedglobal effort.

The announcement of the reviewcomes after antimicrobial resistance waschosen by the public as the winner of the£10 million Longitude Prize, with a focus

Overseas experienceCPE is recognised as a major problem inmany countries in Europe and nearby,such as Greece, Turkey, Spain, Italy andIsrael. Much of the thrust of the Toolkit isin identifying which patients arepotentially at high risk and includeschecking individuals who have recentlytravelled abroad or have had healthcare

to disruption of their normal bowel floramaking it easier for bacteria such as CPEto become established in the bowel,potentially leading to them becominglong-term carriers. It is possible toeradicate MRSA carriage by using topicalantibiotics and antiseptic body washes,but eradication is not feasible with CPE,which are resident in the colon.

can occur after an injury, via the use ofinvasive medical devices that puncture theskin, such as catheters and intravenousdrips, and can then be spread throughfaecal contamination.

Dr John Cunniffe, consultantmicrobiologist at Wirral UniversityTeaching Hospital NHS Foundation Trust,notes that as Gram-negative organisms,CPE bacteria therefore require verydifferent containment and managementstrategies to MRSA, which is Gram-positive. Gram-positive and Gram-negative bacteria are differentiated by theirability to take up Gram staining, whichdepends on the properties of their cellwalls. Many Trusts that historically havehad problems with MRSA and Clostridumdifficile and are now managing theseorganisms effectively still have problemswith CPE.

Once CPE gets a foothold, very highlevels of colonisation will follow,leading to an ‘iceberg effect’ if it is notdealt with extremely quickly, said DrCunniffe. “For every one patient withinfection, there will be another ninecolonised patients who, althoughcarrying the organism in their gut, willshow no adverse effects. If theappropriate infection controls are not inplace and if staff managing the patientare unaware that the individual iscolonised, then these patients arepotentially spreading the bug around.”

As Prof Kerr has noted, theorganism will not just be transmittedaround the hospital. Apparently ‘well’patients will be discharged fromhospital and may spread it to otherhealthy individuals for whomcolonisation will not be a problem, butif a patient carrying CPE returns to anursing home where other residentsmay be vulnerable to infection, thenthis is potentially more serious, as CPEspreads very easily in such individuals,even with good management. This setsup a situation where a patient infectedin a nursing home is sent to hospital,leading to a feedback cycle that caneasily get out of control.

These elderly patients are alsoparticularly vulnerable because theirhealth issues mean they will have had alot of exposure to antibiotics. This leads

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‘Companies are beginning to wise up – if

we do not have new antibiotics and effective

treatments, many of the other therapies they

are developing may be impacted.’Laura Piddock.

‘Without urgent,

coordinated action by

many stakeholders, the

world is headed for a

post-antibiotic era.’

IMI is Europe’s largest public-privateinitiative, which aims to speed up thedevelopment of better and safer medicinesfor patients. With a €2 billion budget, IMIsupports collaborative research projects andworks on building networks of industrialand academic experts in order to boostpharmaceutical innovation in Europe.

In the US, the Biomedical AdvancedResearch and Development Authority(BARDA) also funds private/publicpartnerships, while in the UK the WellcomeTrust has for a number of years beenfunding a ‘seeding drug discovery’ scheme.

Laura Piddock, professor ofmicrobiology at Birmingham Universityand BSAC’s chair in Public Engagement,notes the challenge involved in takingacademic discoveries through to effectivenew drugs for patients. She suggestsseveral other routes, including:• Spin off companies. • Funding from organisations such as the

Wellcome Trust.• Licensing through small/medium

enterprises.• Big pharma.

Prof Piddock believes that bigpharmaceutical companies are now moreopen to funding as they come to recognisemedical need. She said: “Companies arebeginning to wise up – if we don’t havenew antibiotics and effective treatments,many of the other therapies they aredeveloping may be impacted, for examplecancer treatment. Many patients who havecancer will succumb to infection and willneed antibiotics. “I think there’s a tinylight at the end of the tunnel, but we dohave to maintain momentum.” :

References1 www.who.int/drugresistance/documents/

surveillancereport/en2 Farrar J and Woolhouse M.

Nature 29 May 2014; 509: 555-57. 3 www.hpa.org.uk/webw/HPAweb&HPA

webStandard/HPAweb_C/13171403785294 www.bsac.org.uk5 www.hdft.nhs.uk/patients-visitors/

infection-control/hospital-resources/educating-to-reduce-inappropriate-treatment-with-antibiotics

their own initiatives, again focusing oneducation. One example is the EducatingRITA programme (Educating to ReduceInappropriate Treatment with Antibiotics)run by the Harrogate and District NHSFoundation Trust. This consists of a seriesof study days facilitated by members of theprogramme’s team, which includesmicrobiologists, infection control nursesand an antibiotics pharmacist. Forexample, an introductory session focuseson the scale of the antibiotic resistanceproblem using examples from localexperience. Other themes include the useof the microbiology laboratory andunderstanding the concept of bacterialcolonisation as opposed to infection.Failure to differentiate between the twocan lead to an unnecessary course ofantibiotics.5

Prof Kerr commented: “We have to getexisting prescribers to think every timethey reach for the prescription pad. Doesthis patient really need an antibiotic? CanI choose the narrowest spectrum availableand can I keep the course as short aspossible?” He notes that there is aplethora of support for prescribers, suchas advice from consultant microbiologists,antimicrobial pharmacists, and localguidelines, and there are also usefulstrategies such as delayed prescriptions.Point-of-care tests to distinguish betweenstreptococcal sore throat which mayrequire antibiotics and viral infections,which do not, are also available, althoughnot widely used in the UK.

He also emphasised that targetingprescribers is only part of the problem.Good infection control is essential toprevent the spread of infection betweenpatients and healthcare workers. “We need healthcare professionals to takeresponsibility and pride in cleanliness...some Trusts have been so successful ingetting staff to ‘take ownership’ that thereis a healthy competition between wards.”

Antibiotic development Another important piece of the jigsaw is the development of new antibiotics. The huge costs involved for R&D andrelatively low take-up of antibiotics,compared to therapies for heart diseaseand cancer, for example, means that thereis not enough financial reward forpharmaceutical companies to make themassive investments required.

What is now needed are partnershipsbetween the industry, government andNGOs, based on new business models, tomitigate the cost and risks involved. As aresult, new initiatives have begun tospring up, exemplified by the InnovativeMedicines Initiative (IMI), a jointundertaking between the European Unionand the pharmaceutical industryassociation EFPIA.

delivered abroad, in addition to the elderlyand the immunocompromised.

Dr Cunniffe is optimistic that the flurryof recent documents from PHE dealingwith CPE, including a letter to hospitalchief executives,3 is providing anopportunity to get on top of the situation,exemplified by the success of a highly pro-active campaign in Israel. This establishedcentral coordination for reporting ofcases, with an active ‘seek and contain’approach and management of knowncases. This nationwide focus andinvestment resulted in a dramatic drop incases. Levels dropped back down tonumbers seen prior to a recentexponential increase, although not entirelyreaching the baseline. However, Israel hasnot completely got rid of its CPEproblem, retaining some ‘grumbling’activity.

Dr Cunniffe stressed that the UKneeds to put in the appropriate investmentnow, before that exponential increase.“We could actually keep things at a lowlevel, but we have got to get this rightvery, very soon, otherwise we’ll havemissed the boat,” he said.

Antibiotic stewardshipAlongside national strategies such as theCPE Toolkit and the Department ofHealth’s five-year plan, independentnational groups are taking leadership onantibiotic stewardship, with organisationssuch as the British Society ofAntimicrobial Chemotherapy (BSAC),which is running educational events.4

Many hospitals are also developing

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‘Prescribers need to think

carefully. Does the patient

really need an antibiotic?’

About the authorSusan Pearson is a freelance writer,editor and PR consultant specialisinginmedical and environmental issues.

A biology graduate with a degreefrom the University of Bristol, shepreviously worked in medical researchin the Department of Immunology atSt Mary’s Hospital Medical School inLondon.

‘We need healthcare

professionals to take

responsibility and pride

in cleanliness.’

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