This document discusses antimicrobial resistance and provides an overview of several key topics: 1. It outlines various bacterial infections and classes of antibiotics used to treat them, as well as the history and classification of antibiotics. 2. It discusses the growing issue of antimicrobial resistance (AMR), costs and consequences associated with AMR, and examples of "superbugs" demonstrating resistance. 3. It covers interventions and strategies to address AMR, including improved stewardship, surveillance, research and development of new antibiotics, and prevention efforts.

1. David O. Ogbolu
olusogadave@yahoo.com; d.o.ogbolu@bham.ac.uk

2.  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

3.  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

4. Bacterial cells and arrangements

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

6. History of Antibiotics
www.nobelprize.org
• Alexander Fleming in 1928 accidentally
discovers PENICILLIN
• Penicillin quickly became a primary treatment for
pneumonia, diphtheria, syphilis, gonorrhea,
scarlet fever, and many other infections

7.  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

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

9.  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

10.  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

11. 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

12. ‘’the war against diseases has been won’’

13. Antimicrobial Resistance Progression

14. Davies and Davies, 2010; MMBR

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

16.  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

17. Rank Cause of death
Deaths
2002
(in millions)
Percentage
of all deaths
Deaths
1993
(in millions)
1993 Rank
N/A All infectious diseases 14.7 25.9% 16.4 32.2%
1
Lower respiratory
infections
3.9 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

18. Predicted mortality for patients with and without antimicrobial-resistant infection (ARI)
Roberts et al., 2009 Clin Infect Dis.
APACHE score

19.  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

20.  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

21. 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

22.  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

23.  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

24. Numbers of MRSA bacteraemias in England by 6 month periods from 2001 to 2008 (bars, left axis) and
rates of bacteraemia per 10000 bed days (line, right axis)
Livermore, 2009, JAC

25.  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

26.  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

27.  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

28.  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

29.  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

30. (Lewis, 2012
Antibiotic Pipeline

32. New threat from superbugs equipped with NDM-!
Lancet Infect Dis

33. J Assoc Physicians India

36.  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

37.  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

38.  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

39.  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)

40. APUA Field Report: Nigeria. 2013 31(2)

41. 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

42.  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

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

45.  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

46.  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

47. Who is wining the war!!!

48. Antibiotic Action – www.antibiotic-action.com

49. Antimicrobials
Research Group
LAUTECH

50. Thank you!