2. Antibacterial resistance worldwide
Optimism of the early period of antimicrobial discovery
Tempered by the emergence of bacterial strains with resistance to
therapeutics
We enter an era where bacterial infections (bloodstream infections
and ventilator-associated pneumonia) → no longer be successfully
treated with Antibiotics.
We now face a dramatic challenge resulting from two combined
problems:
First, microorganisms are becoming extremely resistant to
existing antibiotics, in particular Gram-negative rods (e.g.,
Escherichia coli, Salmonella spp, Klebsiella spp, Pseudomonas
aeruginosa, Acinetobacter spp), which are resistant to almost all
currently available antibiotics in some settings.
Second, the antibiotic pipeline has become extremely dry

3. 1. Increased Resistance &
Prevalence Worldwide

4. Emergence and dissemination of new
mechanisms of resistance, e.g., novel
extended-spectrum beta-lactamases
(ESBL) and carbapenemases . The
spread of the new resistance gene, the New
Delhi metallo-betalactamase (NDM-1), or
other carbapenemases in
Enterobacteriacae is alarming because
these “superbugs” are resistant to most
available antibiotics and can disseminate
worldwide very rapidly, in particular as a
consequence of medical tourism
Ref: Ready for a world without antibiotics? The Pensières
Antibiotic Resistance Call to Action by Jean Carlet in
Antimicrobial Resistance and Infection Control 2012
http://www.aricjournal.com/content/1/1/11

5. Epidemiology: Global

6. Europe
In Europe, the European Centre for Disease
Prevention and Control (ECDC) reported that
25,000 people die each year from antibiotic-
resistant bacteria.
Multidrug-resistant organisms (MDROs) result in
massive extra healthcare costs and productivity
losses of at least 1.5 billion euros each year in
Europe (Ref: Combating Antimicrobial Resistance: 2011 is the year of
“No action today, No cureTomorrow”
by Daxesh M.P, in Indian Journal of
Pharmacy Practice )

7. USA
In the USA, the annual cost of AMR in hospitals is
estimated at more than US$ 20 billion.
In the US, two thirds of deaths due to bacterial
infections are caused by Gram-negative bacteria
The Canadian Committee on Antibiotic Resistance
developed a model that suggested resistant infections
add $14 to $26 million in direct hospitalization costs
to health care cost in Canada

8. Massive emergence of ESBLs in Ghana
with low socioeconomic income

9. Antibiotic susceptibility proportions for NDM-1-positive
Enterobacteriaceae isolated in the UK and India (Kumarasamyet al.
Lancet Infect Dis 2010)
Antibiotics UK (n=37) Chennai (n=44) Haryana(n=26)
Imipenem
0% 0% 0%
Meropenem 3% 3% 3%
Piperacillin-Tazo 0% 0% 0%
Cefotaxime 0% 0% 0%
Ceftazidime 0% 0% 0%
Cefpirome 0% 0% 0%
Aztreonam 11% 0% 8%
Ciprofloxacin 8% 8% 8%
Gentamicin 3% 3% 3%
Tobramycin 0% 0% 0%
Amikacin 0% 0% 0%
Minocycline 0% 0% 0%
Tigecycline 64% 56% 67%
Colistin 89% 94% 100%

10. ASIA
ESBL-producing bacteria are frequently causing
infections in newborns. In an Indian hospital,
Klebsiella and E.coli were the most common Gram-
negative bacteria among infants with BSIs. About
33% of ESBL-infections were deadly in spite of
available newer antibiotics and other supportive care.
In a study from Pakistan, 37 of 78 newborns (less
than 6 days old) with infections due to Acinetobacter
died within a short time frame. 71% of the bacteria
were resistant to all antibiotics except polymyxin.
Ref: A fact sheet from ReAct - Action on Antibiotic Resistance,www.reactgroup.org, May 2012

11. Initiatives Worldwide
AMR became an important issue in the 1960s when resistance
plasmid and transmissibility were detected.
WHO recognized global AMR threat in 1998
WHO developed the Global Strategy for the containment of
Antimicrobial Resistance in 2001
WHO and member states observed 2011 as the year of
Antimicrobial resistance to building momentum for
rational use of antibiotics: No action today, No cure
tomorrow
The World Health Organization (WHO estimates that up to
40% of health care costs are related to procurement of
medicines.

12. Increased Resistance
Prevalence in India

13. INDIA
ESBL & MBL Prevalence in India:
In 2008-2010, P aeruginosa more resistant against
ceftazidime [53.17%]
Increased resistance to cephotaxime- 50.79%, netilmicin
45.23%, gentamicin - 38.09%, amikacin -36.50%,
ciprofloxacin- 46.82% and piperacillin- 41.26 %.
Among 126 Pseudomonas aeruginosa , 22.22% were ESBL
producers. 69 % strains were resistant to carbapenem.
MBLs in the imipenem resistant isolates was 62.5%.
The study suggested that the carbapenem resistance in P.
aeruginosa was mediated predominantly via MBL
production.
(Source: and MBL Mediated Resistance in Aeruginosa, by Durwas Peshattiwar et al,of
Clinical and Diagnostic Research. 2011)

14. As per a latest report, ESBL production rate was
70% in E. coli and 60% in Klebsiella spp. in
India respectively for the year 2010. (Source: Detection of
TEM and SHV genes in coli pneumoniae in a tertiary care hospital from India, by
Sharma, J et al, J Med )
Very recently in 2011, TEM and CTX-M were
predominantly found in E. coli (39.2%) and
among the Klebsiella spp., TEM, SHV and CTX-
M occurred together in 42.6% of the isolates.
(Source: Correlation of TEM, SHV and CTX-M extended-spectrum beta
lactamases among Enterobacteriaceae with their vitro susceptibility, Manoharan,
A et al, Journal of Medical Microbiology 2011)

15. 2. Declining Antibiotics
Pipeline

16. Dwindling Trend of Antibiotics
Ref: Policy Responces to the growing threat of Antibiotic Resistance in extending the cure.org

17. The FDA approved new antibiotics in the past years (those
with novel mechanisms of action are shaded) (Ref: Policy Responces to
the growing threat of Antibiotic Resistance in extendingthecure.org)

18. Reasons of Dwindling Trend
The antibiotic pipeline is drying up for foll. reasons:
It is intrinsically difficult to find new antibiotics with
novel mechanisms of action.
A high cost/benefit and risk/benefit ratio (length of
development, low selling prices, and short treatments)
discourage pharmaceutical companies from investment.
There is strong competition with other drugs already
on the market. While resistance is an emerging problem,
low-priced generic antibiotics on the market are still
effective in treating most infections and are used as first-
line therapy.

19. Regardless of the reasons → companies have to
deal with the reality → there are less new
products being approved → therefore they are
failing to achieve their potential to provide
treatment for patients and commercial benefits to
their companies.

20. Treatment of ESBL‐producing organisms has become
limited by increasing resistance. However, over 95% of
ESBL‐ producing Enterobacteriaceae are still
susceptible to certain antibiotics → carbepenems,
amikacin, tigecycline and β‐lactam/β‐lactamase inhibitor
combinations.
In some clinical studies, fosfomycin and nitrofurantoin
prove to be good alternatives for urinary tract infections

21. Recent Novel Approaches

22. Novel approaches to developing new
antibiotics for bacterial infections
After more than 50 years of success, the pharmaceutical
industry is now producing too few antibiotics, particularly
against Gram-negative organisms, to replace antibiotics that
are no longer effective for many types of infection.
Genomics, non-culturable bacteria, bacteriophages and
non-multiplying bacteria may also be a source of novel
compounds.

23. Current methods of antibiotic development:
Natural compounds: non-culturable bacteria as target:
Bacteria produce antibiotics that kill or inhibit the replication of competitors. To
date, marketed antibiotics such as streptomycin have been derived from bacteria
that grow on artificial solid or liquid media. Marketed antibiotics have not been
isolated from non-culturable bacteria, since growth on solid media has been an
essential step to the development antibiotics. Now, it is possible to clone large
fragments of non-culturable bacterial genomes and to express them using
recombinant DNA technology
The genomics revolution:
Genomics is used to select potential antibacterial targets and can also be used to
provide insights into, for example, pathogenesis and antibiotic resistance.
GlaxoSmithKline used a genomics-derived, targetbased approach to
antibiotic discovery for 7 years, in which they examined more than 300 genes
and employed 70 highthroughput screening campaigns, but did not develop an
antibiotic into the market (Payne et al., 2007).

24. Bacteriophages
Bacteriophages and their fragments kill bacteria. It is estimated that every 2
days, half of the world’s bacterial population is destroyed by bacteriophages
Bacteriophages have been used as antibacterials in humans in some countries
of the world. Indeed, in the last century, just before the introduction of
penicillin and sulpha drugs, phage preparations were sold in the United
States of America. Even as far as in 2001, bacteriophages were used in
the former Soviet Union to treat patients with infectious diseases.
The development of phage gene products is another potential route for new
antibacterials. Phage lysins, have potential uses as antibacterials for human
use. A particularly interesting finding is that lysins may be active against
non-multiplying bacteria and biofilms. This could help in the treatment
of, for example, catheter-associated infections.
Currently, there is a lack of good human clinical trial results, although
animal studies suggest that in certain circumstances, bacteriophage therapy
may be useful.

25. Non-multiplying bacteria as targets:
Bacteria exist in two different states in a clinical infection, such as
tuberculosis, bacterial endocarditis, biofilms and streptococcal sore throat.
The states are described as multiplying (logarithmic phase) and non-
multiplying (sometimes called stationary phase, dormant or latent).
Currently marketed antibiotics are bacteriostatic for non-multiplying bacteria,
although some of them, such as the penicillins, are highly bactericidal for
multiplying organisms.
The advantage of an antibiotic that is bactericidal for nonmultiplying
bacteria is that the duration of therapy may be shortened. This
presumes that all the multiplying and nonmultiplying target bacteria are
quickly killed by an antibiotic or by a combination of compounds.
(Ref: Novel approaches to developing new antibiotics for bacterial infections
by ARM Coates and Y Hu in British Journal of Pharmacology (2007)

26. Need for Antibiotics
Adjuvant Entities

27. The need for new generations of anti-infective
agents, and in particular new antibacterial agents,
is constant, as the emergence of resistance is largely a
question of when and not if ?
Current antibiotics include the fourth generation of
beta lactams and the third generation of macrolides.
However, significantly new approaches and
strategies for breakthrough molecules have not
been forthcoming.

28. There are examples of recent strategies for
development of adjunctive antibiotic therapies that
overcome microbial resistance and thus rejuvenate the
existing arsenal of drugs.
Recent studies → demonstrated potential of compounds
that inhibit the action of the repressor protein implicated
in ethionamide resistance → stimulating activation of the
drug and thereby restoring the activity of the antibiotic
for treatment of Mycobacterium tuberculosis.
Such specific interference with regulators or signal
transduction mechanisms involved in antibiotic resistance
or virulence → new toolbox for novel combinations of
antimicrobial drugs with adjuvant molecules lacking
intrinsic antibiotic activity.

29. Adjuvant strategies for potentiation of
antibiotics to overcome antimicrobial resistance
(Michel Pieren and Marcel Tigges, Current Opinion in Pharmacology 2012,
www.sciencedirect.com)
The most important defence mechanisms utilized by
bacteria to neutralize antibiotic drug action comprise
Upregulation of active efflux and downregulation of
outer membrane permeability thus inhibiting intracellular
accumulation of the drug,
Antibiotic target mutation,
Enzymatic detoxification of the drug, and
Compensatory pathways that bypass the drug target.

30. Combination therapy regularly used by clinicians
→ suffers from side effects, difficult dosing and the
potential selection of multidrug resistant
phenotypes.
Therefore, combination of an antibiotic with a
non-toxic adjuvant compound → preferable.
Potential points of intervention for such an
adjuvant compound could be → (i) signal
integration and processing, (ii) regulation of
virulence and resistance gene expression, (iii)
activity of effector molecules

31. Prospective Study for Antimicrobial Susceptibility of
Escherichia coli Isolated from Various Clinical Specimens in
India (Manu Chaudhary and Anurag Payasi in J Microb Biochem Technol 4: 157-
160. doi:10.4172/1948-5948.1000088)
Microbial efficacy of a new Antibiotic Adjuvant Entity (AAE),
which is a combination of a non-antibiotic adjuvant Ethylenediamine
Tetraacetic Acid disodium (EDTA) along with β-lactam and β-
lactamase inhibitor, altogether termed as ceftriaxone plus EDTA
plus sulbactam (CSE1034) was studied and compared.
Results obtained in the current research clearly demonstrate the
good in-vitro activity of ceftriaxone plus EDTA plus sulbactam
(CSE1034) against ESBLs, as well as MβLs producing E. coli.
However, penems exhibited in-vitro activity against only ESBLs
producing E. coli.
Hence, in case of infection with MβLs producing E. coli,
ceftriaxone plus EDTA plus sulbactam (CSE1034) can be of drug
of choice for the treatment.