Introduction

Masked Doctors with White Margin The advent of antibiotics for the treatment of infectious disease has been one of the most important advances in modern healthcare, helping save the lives of many hundreds of millions of people since their discovery and widespread use. Currently, more than 100,000 tonnes of antibiotics are consumed each year in human clinical and veterinary practice (Wise. (2002) doi: 10.1093/jac/49.4.585), with antibiotics being the most widely prescribed class of drugs in the world.

  • Heavy Reliance

Unfortunately, this heavy reliance on antibiotics has lead to a global increase in the number of recorded cases of morbidity and mortality from infections caused by antibiotic resistant pathogens, and the World Health Organisation predicts that therapeutic cover will be insufficient within 10 years, with the world being in danger of entering a “post-antibiotic era” in which antibiotics no longer will be an effective option for treating infectious disease. Further, the Centre for Disease Control (CDC), USA, sees antibiotic resistance as “one of the world’s most pressing health problems in the 21 st century” (www.cdc.gov/drugresistance/about.html). Importantly, up to 70% of antibiotics are estimated to be prescribed inappropriately, resulting in severe health and economic outcomes (www.cdc.gov/getsmart/antibiotic-use/fast-facts.html).

With respect to EU countries, antibiotic consumption has also substantially increased during the last decade, though antibiotic consumption tends to vary significantly between EU countries and can reach up to 3.5-fold difference between countries with the lowest and highest consumption. (European Centre for Disease Prevention and Control 2012; http://ecdc.europa.eu/en/eaad/Documents/ESAC-Net-summary-antibiotic-consumption.pdf).

  • Overuse

In the clinical situation, antibiotic overuse results from the inappropriate prescribing of antibiotics to treat non-bacterial diseases (e.g., viral or fungal infections for which antibiotic therapy is ineffective), contributing to both the emergence of antibiotic resistance, as well as unnecessary adverse events (AEs) e.g., allergic reactions, antibiotic-associated diarrhea, intestinal yeast infection, etc. Further, the emergence of antibiotic resistance and AEs adversely impact on patient care and may prolong hospital stay in hospitalized patients. Interestingly, the underuse of antibiotics is also fairly common (15%-40%; Houck et al. Arch Intern Med. 2004. doi: 10.100 lIarchinte.I64.6.637.), and although this may reduce the risk of the emergence of antibiotic resistance and antibiotic-related AEs, such practices may lead to increased morbidity and mortality in patients presenting with bacterial infections but not adequately treated. In fact, the emergence of antimicrobial resistance and AEs may be avoided by early, effective, and targeted (evidence-based) antibiotic treatment therapies by physicians.

  • Respiratory Infections

Respiratory tract infections are among the most common causes of hospital and outpatient visits in the EU, comprising lout of 3 admissions annually (Arias and Murray (2009) doi: 1O.lOS6/NEJMp08046SI). In patients with mild respiratory tract infections, the over prescliption of antibiotics and the use of broad spectrum antibiotics are common practices that may lead to loss of time and resources in patient handling, occurrence of adverse events and the emergence of resistance (www.cdc.gov/drugresistance/about.html). Sepsis-related hospital admissions are less frequent but represent a significant burden to healthcare systems in terms of adverse patient outcomes and the need for rapid, but effective, intervention strategies. In septic patients the key clinical challenge is to ensure that the correct antimicrobial treatment is administered (e.g., an anti-fungal agent for a fungal infection), and that this therapy is administered as soon as possible. Further, only now are newly available molecular methods being made available to physicians in order to provide a better understanding of septic episodes, with the current key problems associated with these approaches being the establishment of large scale collaborations, and the development of analytical algorithms (Wong. Crit Care. 2012 doi: 10. 11 86/cc lOS37). Invasive candida infections are a major burden among hospitalized patients. Invasive candida infections cause 8% of all invasive infections. The case/fatality ratio is 34% (Praller and Diekema. Clin Microbiol Rev 2007. doi: 10.1 I 28/CMR.00029-06u).

  • Identification

One of the main prognostic factors for survival is time to initiation of adequate antifungal therapy (Morrell et a1. AAC 200S. doi: 10.1 I 28/AAC.49.9.3640- 3645.2005). Therefore, timely identification of patients with invasive candida infection is crucial. Further, though an invasive candida prediction rule has been validated for non-neuropenic patients using clinical and colonization parameters, this rule is still far from optimal with an AUROC of 0.63-0.77 depending on the cut-off (Leon et a1. Crit Care Med 2009. doi: 10. I 097/CCM.ObOI 3e3 IS 19daaI4.). Reliable and time-effective microbiological diagnostics are essential for the effective treatment of respiratory infections and sepsis. Conventional approaches have depended upon the cultivation of bacterial and fungal infectious agents with subsequent testing for antibiotic sensitivity and resistance. The processes are necessarily dependent upon lengthy cultivation periods and are not applicable for some bactelial infections, or for many viral infections. Alternative methods of detection have been developed (mainly based on nucleic acid detection), including some commercial systems. These protocols however, exhibit varying degrees of efficacy in confirming pathogens and identifying antibiotic resistance traits, and usually require some information on the organism likely to be causing the infection. In addition, these diagnostic technologies usually require direct sampling of the pathogen. Such sampling is often unfeasible if the infection site is inaccessible (e.g., sinusitis, middle-ear infection, and bronchitis). These diagnostic approaches often suffer from reduced clinical utility because they do not distinguish between pathogenic strains of bacteria/viruses and colonizers, which can be present as part of the natural flora without causing an infection. These limitations lead to a diagnostic gap, which in turn often leads physicians to either overprescribing (“Just-in-case”) or under-prescribing (“watchful waiting”) antibiotics, both of which adversely impact patient care and health economics.

TAILORED-Treatment on the EU HorizonHealth.eu website

EU Health website

TAILORED-Treatment PRESS RELEASE (13/11/2013)

The European Union has funded a 4 year project called TAILORED-Treatment with € 6.000.000,-. The main goal of TAILORED -Treatment is to establish a strategy that can be used to increase the effectiveness of antibiotic treatment, reduce any potential side-effects of therapy, and help limit the emergence of antimicrobial resistance in hospitalized children and adults. The project will be coordinated by Erasmus MC, Rotterdam, the Netherlands.

In the past 70 years, antibiotics have been one of the most important weapons against infectious diseases, Now, unfortunately, antibiotics are the most misused drugs in the world. This misuse has led to the development of a wide range of antibiotic resistances, which now represents one of the major threats to global health.

At the heart of the TAILORED-Treatment project is a clinical study involving hospitalized patients with respiratory tract and/or bloodstream infections, including both children and adults. State-of-the-art diagnostic techniques will be utilised to generate transcriptomic, proteomic, genomic and microbiome data that will be assembled into a single database. This database will then be used to identify novel interactions that characterize both patients and their infections, in order to discover new biological markers of infection and to develop new computer tools that will enable clinicians to better tailor antimicrobial therapy to the individual patient.

One major factor in helping prevent the development and spread of antibiotic resistant bacteria is appropriate antibiotic treatment that is tailored to the pathogen (if any) actually causing disease. However, one of the major problems facing clinicians is deciding which (if any) antibiotic therapy should be prescribed in the 12 to 48 hour period before the causative agent of an infection is identified. Further, patients may die if they are prescribed incorrect antibiotic therapy or if no antibiotic therapy is given. On the other hand, the indiscriminate use of antibiotics, for example in treating viral and fungal infections that do not respond to antibiotics, may lead to the development of antimicrobial resistance, as well as the development of unnecessary side-effects. A method to help clinicians tailor antimicrobial prescribing to individual patients would help reduce the development of antimicrobial resistance and help prevent any unwanted side-effects associated with unnecessary treatment.

TAILORED-Treatment is funded by the EU under the Framework Programme 7 for Health research and coordinated by Erasmus MC (the Netherlands). Partners in the project are: Hadassah Medical Organization (Israel),  University Medical Center Utrecht (The Netherlands),  MeMed Diagnostics Ltd (Israel),  University of Gothenburg  (Sweden), Noray Bioinformatics S.L. (Spain), Ibexperts Ltd (Israel).

EU Grant Agreement No.: HEALTH-F3-602860-2013

TAILORED-Treatment on the Erasmus MC website

TTT on Erasmus MC Drugs Logo