Antibacterial resistance worldwideOptimism 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

1. Increased Resistance & Prevalence Worldwide

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 2012http://www.aricjournal.com/content/1/1/11

Epidemiology: Global

EuropeIn 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 )

USAIn 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

Massive emergence of ESBLs in Ghanawith low socioeconomic income

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)

Imipenem0% 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%

ASIAESBL-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

Initiatives Worldwide

AMR became an important issue in the 1960s when resistance AMR became an important issue in the 1960s when resistance plasmid and transmissibility were detected.plasmid and transmissibility were detected.

WHO recognized global AMR threat in 1998WHO recognized global AMR threat in 1998

WHO developed the Global Strategy for the containment of WHO developed the Global Strategy for the containment of Antimicrobial Resistance in 2001Antimicrobial Resistance in 2001

WHO and member states observed 2011 as the year of WHO and member states observed 2011 as the year of Antimicrobial resistance to building momentum for Antimicrobial resistance to building momentum for rational use of antibiotics: No action today, No cure rational use of antibiotics: No action today, No cure tomorrowtomorrow

The World Health Organization (WHO estimates that up to The World Health Organization (WHO estimates that up to 40% of health care costs are related to procurement of 40% of health care costs are related to procurement of medicines.medicines.

Increased Resistance Prevalence in India

INDIAESBL & 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)

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)

2. Declining Antibiotics Pipeline

Dwindling Trend of Antibiotics

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

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)

Reasons of Dwindling TrendThe 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.

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.

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

Recent Novel Approaches

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.

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).

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.

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)

Need for Antibiotics Adjuvant Entities

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.

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.

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.

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

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.