Pipette and  Petri dishMicrobial infections might represent a potential hazard for the public health, says WHO. But there are very few new molecules in the pipelines to replace traditional antibiotics, and pharma industry is reluctant to invest in the field

Giuliana Miglierini

The WHO’s Antimicrobial Resistance – Global report on surveillance 2014 clearly states that the problem of antibiotic resistance is so serious that it may represent a real danger with respect to the achievements of modern medicine. The lack of new antibiotic drugs is greatly underestimated, not only among the medical practice: pharma industry seems not to be interested in investing in R&D projects to find new molecules able to fight multidrug resistance, one of the main issues to be faced especially in the hospital’s clinical practice. Diseases thought to be eradicated from the Western countries, such as poliomyelitis or tuberculosis, are indeed flourishing again. Even more, they are often able to resist antibiotic treatments, and it’s becoming more and more difficult to find active drugs able to fight against multidrug resistant bacterial strains. Antimicrobial resistance (AMR) is something difficult to perceive in daily life; the WHO’s report is the first official document released by the international Organisation to better define the issue and identify possible instruments to keep it under control.

A wide set of resistant bacteria

The term “antimicrobial resistance” is referred not only to bacteria, but also more generally to microbes able to mutate and to acquire genetic information from other microbes in order to develop resistance. The WHO’s report distinguish four different type of AMR: antibacterial resistance (e.g. to antibiotics and other antibacterial medicines), antiviral resistance (e.g. to anti-HIV medicines), antiparasitic resistance (e.g. to anti-malaria medicines) and antifungal resistance (e.g. in the case of Candidiasis). Mutation is a natural phenomenon affecting all microbes and leading to the survival of the strains able to adapt more efficiently to the new environment; the wide use of antibiotics and other antimicrobial medicines among population has greatly enhanced the appearance of multidrug-resistant strains. Klebsiella, Escherichia coli and Staphylococcus aureus are the most dangerous bacteria to be found in hospitals, while Streptococcus pneumonia, non-thyphoidal Salmonella, Shigella and Neisseria gonorrhoea are widely diffused within the communities (table 1 and 2).

Table 1. Bacteria causing infections in hospitals and communities

Batterium / resistance Typical pathologies (examples) Number of Member States over 194 providing national data Number of WHO regions with national reports of 50% resistance or more
Escherichia colivs 3rd generation cephalosporins

  1. fluoroquinolones
Urinary tract and blood stream infections 8692 5/65/6
Klebsiella pneumoniaevs 3rd generation cephalosporins

  1. carbapenems
Pneumonia, urinary tract and blood stream infections 8771 6/62/6
Staphylococcus aureusvs methicillin MRSA Wound and blood stream infections 85 5/6

fonte: WHO, Antimicrobial resistance – Global report on surveillance 2014


Table 2. Bacteria mainly causing infections in the community

Batterium / resistance Typical pathologies (examples) Number of Member States over 194 providing national data Number of WHO regions with national reports of 50% resistance or more
Streptococcus pneumoniaenon susceptible to penicillin Pneumonia, meningitis, otitis 67 6/6
Nonthyphoidal Salmonellavs fluoroquinolones

  1. carbapenems
Foodborne diarroea, blood stream infections 68 3/6
Shigella speciesvs fluoroquinolones Diarroea (‘bacillary dysenteria’) 35 2/6
Neisseria gonorrehoea- vs 3rd generation cephalosporins Gonorrhoea 42 3/6

fonte: WHO, Antimicrobial resistance – Global report on surveillance 2014

The risk of death is markedly higher for patients infected by resistant bacteria compared to the susceptible ones: 23,6% vs. 12.6% in the case of E.coli infections treated with third generation cephalosporins, 20% vs. 10.1% for Klebsiella infection treated with third generation cephalosporins and 27% vs. 13,6% for the carbapenems’ treated ones, 26,3% vs. 16,9% for the S. aureus infections treated with methicillin (WHO data). The report indicates in 25.000 the deaths per year in the European Union due to microbial infections, with 2,5 mln extra hospital days and overall societal costs for approx. € 1.5 bln per year plus € 900 mln for hospital days. In the United States the situation is similar: more than 23.000 deaths and up to $ 20 bln direct costs plus $ 35 bln undirect costs.

Antibacterial resistance

The 2014 Global Report focus its attention on antibacterial resistance (ABR) as the first goal to be pursued, as global surveillance in this field is far less developed compared to that for diseases such as tuberculosis, malaria or HIV and effective treatment options are running out. ABR is widely involved in the diffusion of quite common pathologies, such as urinary tract infections, especially within hospitals. WHO highlights the lack of agreement on surveillance standards and on the analysis and sharing of data and suggests some actions to be undertaken in order to strengthen the surveillance network and inform decision-making. (BOX 1).

But the issue on how to better deal with ABR is not simply limited to the improvement of the surveillance strategy: the lack of new active antibacterial medicines is becoming an outstanding health threat. UK’s prime minister Mr David Cameron announced a special commission – guided by economist Jim O’Neill and including experts from industry, science and regulatory authorities – will investigate the reasons why pharma pipelines do not comprise promising new antibiotics. We are facing a “possible Middle Age for medicine”, said Mr Cameron. Results of the working group should be presented, according to UK’s prime minister, during the G7 scheduled in Germany in 2015.

Why pharma is not investing in antibiotic research

Bacterial infections usually call for short term treatment options: a typical cycle of antibiotic intervention lasts just for one week, and even if the number of potential patients is quite high, the market for antibacterial medicines is not so big to represent a real economic interest for pharma industry, much more oriented towards investing in life-long treatments for chronic diseases.

Gianni RezzaPharmaWorld has interviewed Gianni Rezza, MD, head of the Center for infectious diseases of the Italian Institute of Health. «Research on new antibiotics stopped because the commercial interest decreased. The investments required to develop a new drug are very high. Bacterial infections do not last for life, even if they affect a wide part of the population. The market might be quite interesting. The consequence is the lack of available antib
iotics, and of new candidates in the pipelines. A tighter collaboration between private companies and public institutions could help to revamp the research in the field
», commented Mr Rezza.

Great Britain and Switzerland are among the countries more involved in the research for new antibiotics, as a result in the increasing investments in R&D activities for orphan and neglected diseases. «Several consortia have been created in order to find new products. Often the innovation potential is found in public research, but then there is need for the private intervention in order to fully develop it. In Italy is even more difficult to create new partnerships between private and institutional actors», further explained Mr Rezza. An example of such collaboration in Italy is represented by the CNCCS (Collezione Nazionale di Composti Chimici e Centro Screening) initiative, born in 2010 and involving the IRBM Science Park, the Italian National Research Council and the national Institute of Health (BOX 2).

Multidrug-resistance is particularly difficult to handle in the case, for example, of tuberculosis, a disease considered to be eradicated in the Western countries but currently representing an increasing issue also due to the increasing number of people moving to Europe from North Africa and Near East countries as consequence of the many conflicts in these regions. «There are now some extra-resistant strains of tuberculosis and we shall need new medicines to treat patients unresponsive to available drugs. It’s quite a serious problem that would call for R&D activities», said Mr Rezza.

Klebsiella infections are also a great hazard especially in the hospitals; new resistant strains have been identified as being imported from India and UK. «Multidrug-resistant Klebsiella is present in many intensive care departments. These strains are often sensitive just to one drug. Acinetobacter infections too represent an issue, but at a lower degree than Klebsiella», said the expert.

The correct use of antibiotics

Antibacterial medicines are often prescribed in the clinical practice even if there is not a real need for them: flu or cold, for example, are viral pathologies not responsive to antibiotics. They are often prescribed as a preventive measure against the possibility of bacterial over-infections, especially in the case of old or weak people. This incorrect use of antibiotics is one of the main causes of drug resistance, as bacteria rapidly mutate to adapt to the intervention and transmit to progeny the improved genomic characteristics. Health authorities worldwide have invested in communication campaigns to inform about the correct use of antibacterial as a primary way to fight against multidrug resistant infections. «As a result, the over-use of antibiotics is decreased. Greece, Italy and South Europe countries are the bigger consumers. But the real problem is not an over-prescription, but indeed a too often not adequate one. We often see new generation antibiotics prescribed in the case of flu; dosages also are often wrong or there is no request for an antibiogram analysis prior to prescribe the medicine. These are all examples of an incorrect use of antibiotics that might be responsible for the selection of resistant strains», explains Mr Rezza.

The WHO’s report is a first important step towards a better way to address antibacterial resistance, not only in humans but also in animals, as food-producing animals and food products are a possible vector for the spreading of the resistance. Further international actions, propose WHO, shall focus in establishing new standards and a collaborative platform for global surveillance, in order to support a better monitoring capacity and inform decision-making.



Some issues to be addressed in fighting AMR

The WHO’s Antimicrobial resistance 2014 Global report propose several actions to be taken in order to fight AMR, following the already implemented example of the epidemiologically sound surveillance systems established for tuberculosis, malaria and HIV/influenza to monitor resistance and disease impact. This system has taken many years to build and is dependant on external funding; available information verifies that AMR is increasing.

Major gaps exist in surveillance and data sharing in food chain and food-producing animals, calling for integrated surveillance systems and implemented global standards. WHO is pursuing a multi-sectorial approach by collaborating with the Food and Agriculture Organization (FAO), the World Organisation for Animal Health (OIE) and other stakeholders.

Invasive Candidiasis is also a major burden: antifungal resistance to fluconazole varies widely by country and species and resistance to newest class of antifungals (echinocandins) is emerging.

Fonte: WHO – Antimicrobial Resistance – Global report on surveillance 2014



The Italian tradition in antibiotic’s R&D

Some of the historical and widespread antibacterial medicines were originated by the Italian pharmaceutical industry. Companies such as Lepetit did not survive the M&A round in the ‘90, but their excellence and tradition in the research of new antimicrobial molecules is still alive. The Fondazione Istituto Insubrico di Ricerca per la Vita, based in Gerenzano, has inherited from Pfizer Vicuron the top level know-how of Lepetit: more than 15 thousands bacterial strains, 166 thousands extracts and a chemical library of more than 100 thousands molecules obtained by chemical synthesis, fully structurally characterised and waiting for biological assay. The Fondazione hold some more 30 thousand proprietary extracts from rare actinomycetes, fungi and eubacteria.

The Pomezia pharma district host the recently founded (2010) Collezione nazionale di Composti chimici e centro Screening (CNCCS), a public-private consortium aiming to create an European collection of chemical substances associated to an HTS screening center, in order to identify new candidates active on biological targets. The institute collects newly synthetized compounds from public and private labs and test them so to accelerate the discovery of molecules active on genetic function, on biological mechanisms or as new medicines for rare and neglected diseases.

Fonte: Fondazione Istituto Insubrico di ricerche per la vita e Collezione nazionale di Composti chimici e centro screening (CNCCS)