Antibiotic resistance: how did we get here and what can we do? Peter Lambert LHS

Antibiotic resistance: how did we get here and what can we do? Peter Lambert LHS

How do we diagnose and treat infection?

Organisms are cultured and identified

Microscopy gives a clue to identity Staphylococcus aureus Escherichia coli

Identity confirmed by biochemical profile

Antibiotic sensitivity testing isolation, identification and sensitivity testing takes time

Automated sample processing

Automated identification

Identification by mass spectrometry (MALDI-TOF)

Automated antibiotic sensitivity testing But it still takes time to identify and find the most effective antibiotic

Selection of antibiotics for treatment Empirical therapy initially Isolate and identify the organism Determine its sensitivity to antibiotics Treat with an appropriate antibiotic Over 100 antibiotics are available (~12 major groups) We expect all infections to be treatable But for how much longer?

the major groups of antibiotics were identified in the golden age of discovery : Many have been modified to improve their performance but few new classes of antibiotics have been discovered since 1960

By 1969 many experts were confident the tide had turned in the war against bacterial infections US Surgeon General, William Stewart, told the US Congress it was time to close the books on infectious diseases.. Most of the Pharmaceutical Industry stopped working on new classes of antibiotics But the microbes had not been defeated Resistance was emerging..

A warning from Alexander Fleming s Nobel Prize speech in 1945 It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.

The problem of antibiotic resistance Mutations drive resistance Mutations occur in around one in a million cells If a mutation results in resistance.. Using antibiotics will select for resistance.. and. resistance genes can be transferred to other bacteria

Antibiotic resistance mechanisms exclusion changes in targets efflux Antibiotic inactivation Altered or acquired resistance genes Microbes use each of these mechanisms (often in combination) to resist antibiotic action

Resistance encountered following discovery

Antibiotic resistance reduces treatment options: example Staphylococcus aureus Penicillin resistance in Staphylococcus aureus is due to production of enzymes (penicillinases) that destroy penicillin Methicillin and flucloxacillin were developed to overcome this resistance. but resistance to these soon emerged..

Methicillin Resistant Staphylococcus aureus First described in 1961 Emerged as a hospital pathogen 1970s Rapid spread in hospitals 1980s-1990s (50%) Hospital patients and elderly at risk Community strains infect healthy individuals MRSA the first superbug had arrived

What is MRSA? Staphylococcus aureus resistant to methicillin (and flucloxacillin) 30% of the population carry S. aureus 1-3% of the population carry MRSA Found in hospitals / community Transmission: patient to patient; environment to patient; health care worker to patient Some are particularly invasive (USA 300)

MRSA the first of the superbugs Staphylococcus aureus MRSA Sensitive to methicillin and flucloxacillin Resistant to methicillin and flucloxacillin

Why are MRSA strains resistant to methicillin and flucloxacillin? MRSA had acquired extra DNA (the meca gene) encoding a resistant penicillin target MRSA could be treated with vancomycin, however. Vancomycin resistance was already common in related microbes (van genes in enterococci) Could MRSA acquire the van genes from enterococci and become resistant to vancomycin?

Vancomycin resistant MRSA First demonstrated in the lab in 1992 First clinical strains with reduced sensitivity to vancomycin were isolated in Japan in 1996 They posses the meca gene AND their cell wall is thicker than usual, preventing vancomycin from reaching its target MRSA VISA

But could MRSA become totally resistant to vancomycin? First fully resistant clinical strains (VRSA) were isolated in USA in 2002 They have the meca gene AND the vana genes which encode for an altered (resistant) cell wall 13 VRSA have been reported in USA, others in Portugal and Brazil Fortunately they could be treated with other antibiotics but resistance to these could follow..

MRSA death rates in England and Wales Urgent action was needed to bring these soaring MRSA rates under control Office for National Statistics

Health Secretary John Reid (Nov 2004): Bloodborne MRSA infection rates to be halved by 2008 Keep hospitals clean Effective hand hygiene Use antibiotics carefully Keep a close track on MRSA in hospitals and the community Screen for MRSA on admission Mandatory infection control training Increase public awareness staff and visitor compliance

The measures worked! 85% reduction in MRSA but. other resistant organisms were taking their place. Office for National Statistics report 2013

Enterobacteriaceae, the new superbugs Escherichia coli and Klebsiella pneumoniae are Enterobacteriaceae (family of Gram-negative bacteria that originate from the gut)

Enterobacteriaceae, the new superbugs 44% of bloodstream infections in UK are E. coli or K. pneumoniae 10-20% are resistant to multiple antibiotics In the UK 5000 patients die each year from sepsis due to these and related Gram-negative bacteria Acute hospitals report 50-100 cases for every MRSA

Why are they resistant? Widespread use of cephalosporins in 1980-90s selected for strains producing enzymes that break down cephalosporins (ESBLs) These were treated with carbapenems, the most active of all antibiotics (and should be reserved to treat the most serious infections)

Carbapenem Resistant Enterobacteriaceae Over-use of carbapenems has selected for E. coli and Klebsiella strains producing enzymes that break down carbapenems The big five enzymes: NDM-1, KPC, OXA, VIM, IMP These Carbapenem Resistant Enterobacteriaceae (CRE) are true superbugs Spreading worldwide, healthcare and residential settings.. Limited treatment options.. 50% mortality, a nightmare scenario. They keep Consultant Microbiologists awake at night..

Spread of KPC Klebsiella pneumoniae 2000 KPC identified in North Carolina from a 1996 isolate 2003 New York KPC outbreak 2005 KPC in Israel, UK, Sweden, Italy, Columbia

Worldwide spread of NDM-1 CRE 2008 NDM-1 in Sweden, patient had been treated in New Delhi cases in UK and USA linked to India and continued to spread

Rapid emergence of all CRE in UK

Few treatment options remain for CRE Some isolates are sensitive only to colistin Mcr-1 colistin resistance gene reported on plasmid in China, Denmark and UK

Management and control of CRE 2014 Prevention and control of multi-drug-resistant Gram-negative bacteria: recommendations from a Joint Working Party. Wilson A P R et al., J Hospital Infection (2016) 92 S1-44

Chief Medical Officer England Prof Dame Sally Davies, 2013 "Antimicrobial resistance poses a catastrophic threat "we will find ourselves in a health system not dissimilar to the early 19th century at some point" "If we don't act now, any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can't be treated by antibiotics routine operations like hip replacements or organ transplants could be deadly because of the risk of infection ticking time bomb.nightmare.as serious as terrorism.

Jim O Neill, Chair of Review on Antimicrobial Resistance: 2014 Tackling a crisis for the health and wealth of nations Predicts 10 million extra deaths per year by 2050, costing $100 trillion Proposes 5 steps to tackle AMR: $2bn Global AMR innovation fund Get most from existing drugs Improve diagnostics High calibre skills base Global surveillance

Review on Antimicrobial Resistance: 2015 5 further reports on ways to tackle AMR: Tackling a global health crisis initial steps Securing new drugs for future generations Rapid diagnostics: stopping unnecessary use of antibiotics Safe, secure and controlled management of the supply chain of antimicrobials Antimicrobials in agriculture and the environment for the health and wealth of nations

USA National Action Plan, 2015 Two million illnesses 23,000 deaths from antibioticresistant "superbugs" each year in the United States 5 year national action plan $1.2bn slow the growth and spread of superbugs by reducing the use of antibiotics when they are not needed 50% reduction in inappropriate antibiotic use in doctor's offices 20% reduction in hospital use by 2020

Generating Antibiotic Incentives Now (GAIN) GAIN provisions introduced 2012 Extend by five years the exclusivity period during which certain antibiotics those that treat serious or life-threatening infections can be sold without generic competition. This increases the potential for profits from new antibiotics by giving more time to recoup investment costs

Recent antibiotics approved by FDA Avycaz (ceftazidime/avibactam) Zerbaxa (ceftolozane/tazobactam) Dalvance (dalvabancin) Sivextro (tedizolid) Orbactiv (oritavancin) Pipeline: 36 new antibiotics in development: 10 in Phase 1 clinical trials 18 in Phase 2 8 in Phase 3

Some thoughts on the way forward We cannot defeat bacteria, resistance will always emerge, but we can try to keep ahead of resistance: improve diagnostics (use existing antibiotics more carefully) modify antibiotics to counter resistance develop anti-resistance agents discover new classes of antibiotics natural antimicrobial peptides gene silencing: anti-sense, anti-gene gene editing enzymes: CRISPR/Cas9 bacterial predators: bacteriophage, Bdellovibrio light-activated therapy (direct or via photo-sensitizer)

Smart screening Kim Lewis, Boston, uses ichip soil diffusion cell to culture newly recognised soil bacteria Eleftheria terrae produces a new antibiotic Teixobactin. Active vs MRSA, enterococci but not CRE

Activation of silent antibiotic genes Most of the antibiotic genes in Streptomyces species are not expressed in lab media

CRISPR/Cas9 targeting resistance genes Citorik RJ et al Nature Biotechnology (2014) 32, 1141 1145 Bikard D et al Nature Biotechnology (2014) 32, 1146 1150

Bacterial predators: Bacteriophage (Novolytics/Cobra Biologics) Bdellovibrio bacteriovorus

Topical PDT in dentistry and podiatry Periowave (Ondine Biomedical) PACT fungal nail therapy (Toetal Footcare)

Is this the end of antibiotics? No, but we must take action now antibiotic resistance is a global health problem requires international attention and collaboration bacteria do not recognize borders..