Threat of antibiotic resistant bacteria to humans

David O. [email protected]; [email protected]

Bacterial classes Infectious diseases History & Classes of antibiotics Antimicrobial resistance (AMR) Consequences/Costs of AMR Superbugs & Super-resistance Alerts on AMR Interventions of AMR Causes & Prevention of AMR Concluding remarks

1. A statement of an intention to inflict pain, injury, damage, or other hostile action on someone in retribution for something done or not

2. A person or thing likely to cause damage or danger

Oxford

Bacterial cells and arrangements

Tuberculosis Urinary tract infection Gastrointestinal tract infection Sepsis Surgical wound infection Pneumonia Skin and soft tissue infection

History of Antibiotics

www.nobelprize.org

• Alexander Fleming in 1928 accidentallydiscovers PENICILLIN• Penicillin quickly became a primary treatment for pneumonia, diphtheria, syphilis, gonorrhea, scarlet fever, and many other infections

Antibacterial antibiotics are commonly classified based on ◦ Mechanism of action

Those that target the bacterial cell wall Cell membrane interfere with essential bacterial enzymes Those that target protein synthesis

◦ Chemical structure Compounds isolated from living organisms Semi synthetic Synthetic

◦ Spectrum/Biological activity Narrow-spectrum" antibacterial antibiotics target specific types of

bacteria, such as Gram negative or Gram positive bacteria Whereas broad-spectrum antibiotics affect a wide range of

bacteria

◦ Or use based on local application First-line antibiotics Second-line agents Third-line antibiotics

Penicillin and cephalosporins Carbapenems Polymixins Quinolones and Fluoroquinolones Sulphonamide Macrolides Tetracyclines Aminoglycosides Lipopeptides Glycylcyclines Oxazolidinones

There are about 209 marketed antibiotics for the treatment of bacterial and fungal infections

Of these 209 marketed antibiotics, 87 (42%) are classified as beta lactams (carbapenems, cephalosporins, monobactams and penicillins).

Lack of innovation in the development of new antibiotic molecules has increased greatly the challenge of treating and eradicating certain infecting pathogens

Biopharm, 2012

Antimicrobial resistance occurs when bacteria changes in ways that reduces/eliminates the effectiveness of the drug designed to cure/prevent the infection

Antibacteria resistance is currently recognised as a major medical challenge

Resistance is also evident in other microorganisms-namely;

Parasites Fungi And viruses

Hospital

MRSA Glycopeptide-resistant

enterococci (GRE) Enterobacteriaceae with

extended spectrum ß-lactamases (ESBLs) or carbapenemases

Pseudomonas aeruginosa Stenotrophomonas

maltophilia Acinetobacter baumannii

Community

Mycobacterium tuberculosis

Neisseria gonorrhoeae Streptococcus

pneumoniae Salmonella enterica Group A streptococci CA-MRSA

Boundary becoming increasingly blurred

Adapted from LJV Piddock, 2013

‘’the war against diseases has been won’’

Antimicrobial Resistance Progression

Davies and Davies, 2010; MMBR

Drug resistance is so common and the term can be described in so many ways;◦ MDR◦ XDR◦ PDR

Mortality ◦ In Europe, 25,000 people die every year from drug-

resistant infections Morbidity

◦ Prolonged illness◦ 2.5 million extra in hospital days◦ Greater chance of resistant organisms to spread to others

Cost◦ 1.6 billion Euros extra cost◦ 600 millions days of loss of productivity

Limited Options◦ Few new drugs on the horizon

Rank Cause of death

Deaths2002(in millions)

Percentageof all deaths

Deaths1993(in millions)

1993 Rank

N/A All infectious diseases 14.7 25.9% 16.4 32.2%

1Lower respiratory

infections3.9 6.9% 4.1 1

2 HIV/AIDS 2.8 4.9% 0.7 7

3 Diarrheal diseases 1.8 3.2% 3.0 2

4 Tuberculosis (TB) 1.6 2.7% 2.7 3

5 Malaria 1.3 2.2% 2.0 4

6 Measles 0.6 1.1% 1.1 5

7 Pertussis 0.29 0.5% 0.36 7

8 Tetanus 0.21 0.4% 0.15 12

9 Meningitis 0.17 0.3% 0.25 8

Worldwide Mortality due to Infectious Diseases

Predicted mortality for patients with and without antimicrobial-resistant infection (ARI)

Roberts et al., 2009 Clin Infect Dis.

APACHE score

The term “superbugs” refers to microbes with enhanced morbidity and mortality

In some cases, super-resistant strains have also acquired increased virulence and enhanced transmissibility

Realistically, antibiotic resistance can be considered a virulence factor

Gram-negative bacteria are highly efficient in developing mechanisms of antimicrobial resistance

Klebsiella pneumoniae, which causes many types of healthcare-associated infections, including pneumonia, urinary tract infections, and bloodstream infections

E. coli, which causes the majority of urinary tract infections

Pseudomonas aeruginosa has evolved from being a burn wound infection into a major nosocomial threat

Acinetobacter baumannii is a more recent Gram-negative pathogen and is also primarily nosocomial are sometimes resistant to all antibiotics

Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhea, the second most commonly reported infectious disease in the United States

Rise in the proportions of E. coli from bacteraemias in England, Wales and Northern Ireland resistant to fluoroquinolones (white), oxyimino-cephalosporins (grey) and both (black)

Livermore, 2009 JAC

Gram-positive organism Staphylococcus aureus enjoyed extensive press coverage over the years

S. aureus has a close association with humankind: it is carried as a nasal commensal in 30% of the population

Its presence has long been linked to common skin infections such as boils

Although, it does not have the historical reputation of M. tuberculosis, but in recent years, this multidrug-resistant pathogen has emerged as one of the major nosocomial infections

The landmark discovery and introduction of methicillin in 1959 were thought to be a sure defense against the penicillinases

The appearance of methicillin-resistant S. aureus (MRSA) within just 3 years led inexorably to other multiantibiotic-resistant variants

MRSA has moved outside the hospital and become a major community-acquired (CA) pathogen, with enhanced virulence and transmission characteristics

In 2004, 40-60% S. aureus strains are MRSA and usually MDR with low level resistance to vancomycin

Treatment failures lead to more death with MRSA and use of more reserved drugs

DeLeo et al., 2009; J Clin Invest

Numbers of MRSA bacteraemias in England by 6 month periods from 2001 to 2008 (bars, left axis) and rates of bacteraemia per 10 000 bed days (line, right axis)

Livermore, 2009, JAC

A long-recognized hospital denizen, the toxin-producing anaerobe Clostridium difficile, is increasingly found as the cause of severe intestinal infections

Hypervirulent toxin-producing strains have been recognized

Being a Gram-positive spore former, it is a hardy organism and is readily transmitted by hospital personnel, on equipment, and as aerosols

Its renewed prominence is considered the result of extensive hospital use of antibiotics such as expanded-spectrum cephalosporins, the newer penicillins, and fluoroquinolones

In other words, these infections are the direct result of antibiotic use

Tuberculosis is a leading cause of death 8 million people develop active TB yearly with 1.7 million dying

TB was considered conquered in Europe due to the ground-breaking discoveries of streptomycin and isoniazid

Resistance development was rapid and TB re-emerged as a major public health problem

However for a variety of reasons multidrug resistance continues to compromise TB therapy throughout the world

M. tuberculosis strains resistant to four or more of the front-line treatments- XDR strains) have appeared and spread rapidly in the last decade

And now there are TDR strains, which are totally drug resistant!

Fears et al., 2010

M. tuberculosis strains resistant to four or more of the front-line treatments (i.e., extremely drug-resistant [XDR] strains) have appeared and spread rapidly in the last decade or so

And now there are TDR strains, which are totally drug resistant!

No effective treatment or prevention after 2 decades of WHO declaration of TB as a global emergency

Other serious infections include nosocomial (hospital-linked) infections with;

◦ Burkholderia cepacia, Campylobacter jejuni, Citrobacter freundii, Enterobacter spp., Enterococcus faecium, Enterococcus faecalis, Haemophilus influenzae, Proteus mirabilis, Serratia spp., Staphylococcus epidermidis, Stenotrophomonas maltophilia, and Streptococcus pneumoniae

109 candidate antibiotics in the clinical pipeline

Approximately 70% of which are in early development (Preclinical and Phase 1)

In contrast, there are just 9 candidates at Phase 3, while there are 31 at Phase 2

These pipeline developments are being progressed by 66 companies

Nine (14%) are major international corporations and 57 (86%) are Small/Medium Sized Enterprises (SMEs)

Biopharm, 2012

(Lewis, 2012

Antibiotic Pipeline

New threat from superbugs equipped with NDM-!

Lancet Infect Dis

J Assoc Physicians India

WHO 2009: “Antibiotic resistance - one of the three greatest threats to human health”

WHO World Health Day. 7 April 2011: Antimicrobial resistance: no action today, no cure tomorrow

Margaret Chan, Director General, WHO, September 2012 “If health fails, all else fails”

Adapted from LJV Piddock, 2013

The range of topics discussed was broad and included; urbanisation, pollution, climate change, biodiversity, ageing population, etc

The need to combat antimicrobial drug resistance was given a high profile despite considerable attention AMR has received in the UK

Importance of international agreements and complementary policies were reiterated

Working with existing agencies such as the WHO for emergence of effective tools

The Biologist, 2013

Improve how we prevent and manage infections in people and in animals

Improve education and training around the prescribing of antibiotics to reduce inappropriate

Collect better data on the resistance of bugs so we can track them more effectively

Provide funding of up to £4million to set up a new National Institute of Health Research (NIHR) Health Protection Research Unit which will focus on AMR and healthcare associated infections

Explore ways to encourage the development of new antibiotics, rapid diagnostics, etc

Department of Health, Sep. 2013

Antibiotic Resistance Monitoring & Reference Laboratory (ARMRL)

The Stop TB Partnership The Center for Diseases Dynamics,

Economics & Policy European Antimicrobial Resistance

Surveillance Network (EARS-Net) National Institute of Allergy and Infectious

Diseases (NIAID) International Network for the Study and

Prevention of Emerging Antimicrobial Resistance (INSPEAR)

APUA Field Report: Nigeria. 2013 31(2)

MICs of recipient strains after transfer of VIM, NDM or unknown carbapenemases

Strain

Gene(s)a Minimum Inhibitory Concentrations, MIC (mg/L)

IPM MPM ETP CAZ CIP AZT NAL COL AK CHL GEN TIG

Donor

U36 VIM >64 32 >64 >64 32 8 >64 32 >64 >64 >64 32

U37 VIM/NDM 16 16 64 >64 >64 >64 >64 1 >64 >64 >64 2

U28 unknown 16 16 >64 >64 >64 16 >64 4 32 >64 >64 2

Representative transconjugates/transformants

T-U36 VIM 1 4 16 >64 0.25 >64 >64 ND >64 32 >64 0.5

T-U37 NDM 2 4 4 >64 8 >64 >64 ND 1 2 8 0.25

T-U28 unknown 8 16 >64 2 2 32 16 ND 1 16 8 0.25

Control strain

NCTC 10418

0.12 <0.03 <0.03 <0.03 <0.03 0.03 1 0.12 1 2 0.5 0.06

Use of antibiotics Inadequate infection control practices Lack of interest by pharmaceutical companies

in research and development of new drugs Use of antibiotics in food animals and

agriculture Intrinsic nature of some bacteria Uncontrolled release of antibacterial

compounds into the environment International travel, trade, adoption all

facilitate the globalization of antimicrobial resistance

The AIDS epidemics and other types of immunocompromise diseases

Drugs already in market Daptomycin Linezolid Alvimopan Fidaxomicin TigecyclineDrugs at different stages of clinical trial Ceftolozane/tazobactam Surotomycin Bevenopran AYX1

Novel antimicrobial agents Use of natural products Combinational therapy Vaccines Immunomodulatory agents Probiotics Bacteriophage therapy Control of all antibiotic treatments Effective surveillance systems for early detection

of AMR Improvement of heathcare provider and public

education Robust research to guide the previously

mentioned action

Resistance is inevitable- The problem of resistance accompanies the use of NEW drugs

The simple UNPOPULAR thorough washing of hands

View antibiotic resistance as a global crisis akin to AIDS

Who is wining the war!!!

Antibiotic Action – www.antibiotic-action.com

Antimicrobials Research Group

LAUTECH

Thank you!