Dramatic Shortage of Therapeutic Options
Resistance of bacteria against antimicrobial agents is acquired through several mechanisms including spontaneous mutations and transfer of genetic material. Furthermore, once they have been acquired, the resistance mechanisms may be transferred from one bacterium to another or from one bacterial species to another, Thus, there is a continuous challenge for the pharmaceutical industry to provide novel antibiotics which are active against the most recently acquired resistance mechanisms.
Resistance per se is necessary for bacteria to defend themselves against antimicrobials produced by their competitors in their environment. The occurrence of resistance against man-made antimicrobials is therefore not surprising and was recorded shortly after the introduction of the first antibiotics into human medicine. The situation has, however, worsened during the last decades.
With increased use of methicillin in Gram-positive bacteria infections, resistant Staphylococcus aureus (commonly referred to as MRSA) were observed. Today, rates of MRSA as high as 60 - 70% of invasive isolates are recorded in some hospital settings abroad. With nearly 20% MRSA, Germany had an intermediate rate in 2006, according to the EARSS website1 (for comparison: Greece: ca. 43%, UK ca. 42 %, Sweden below 1%). As a consequence, use of vancomycin, an antibiotic which for a long time served as a last resort, increased sharply since the mid eighties. A few years later, first isolates of MRSA showed decreased susceptibility to vancomycin and the first resistant isolates were observed shortly thereafter. In addition, emergence of vancomycin resistant enterococci is a major problem in hospital settings.
An elegant way to reduce resistance development is the treatment with combinations of antimicrobials. Combination therapies with up to four potent antimicrobials are the standard therapy for patients suffering tuberculosis (caused by Mycobacterium tuberculosis, a bacterium with a very lipid rich cell wall). However, lack of compliance and limited availability of such tuberculostatic drugs has led to the occurrence of mycobacteria with single or double resistance against the most potent drugs, followed by multi-drug resistant (MDR) tuberculosis. In some regions of the world (Eastern Europe, Asia), WHO2 reports about 15% of all new tuberculosis cases to be caused by MDR M. tuberculosis. In 2006, first mycobacteria with an even worse phenotype have been recorded called XDR (for extended or extremely resistant). Although rare at this time, lethality of infections with XDR M. tuberculosis was unprecedentedly high.
For Gram-negative bacteria, the situation is no better. Some of the most frequently isolated Gram-negative bacteria like Klebsiella pneumoniae or Escherichia coli now impress with extended spectrum beta lactamases, enzymes hydrolysing the beta lactam ring of the identically named antimicrobials (e.g.~14% of invasive K.. pneumoniae isolates showed resistance against 3rd generation cephalosporins in 2006 according to EARSS). These bacteria are called ESBL and are clinically resistant against most of the beta lactams antibiotics. In addition, quinolone resistance is on the rise in E. coli, shortening therapeutic options even further. In Germany, nearly 30% of E. coli were found to be resistant against at least one of the fluoroquinolones currently in use. Pan-resistant isolates of Pseudomonas aeruginosa and Acinetobacter have been recorded but are still rare. However, in spite of the high medical need for resistance breaking antibiotics for Gram-negative bacteria, only very few antimicrobials are under investigation, mostly from already known classes.
Links
1 The European Antimicrobial Resistance Surveillance System
2 World Health Organisation
