Bacteria as pathogens

Bacteria are micrometers small unicellular organisms that, with a few exceptions, are only visible under the microscope but, unlike viruses, have their own metabolism. Although thousands of different bacterial species have been described and systematically classified in the approximately 350 years since the discovery of these microorganisms, it can be assumed that the vast majority – 95 to 99 percent – of all bacterial species existing on earth are not yet known.

 

In nature, bacteria occur in large numbers in practically every conceivable environment, in soil, earth crust, air, fresh and salt water. Humans, too, are colonized by numerous bacterial species. It is estimated that on its outer and inner surfaces it contains about 1014 to 1015 bacterial cells as so-called “normal flora” or “microbiome”. While about 1,000 germs per cm2 can be detected on the skin, significantly higher bacterial densities can be found on the mucous membranes of other parts of the body, for example in the mouth, throat or vagina. However, the largest concentration of bacteria can be found in the large intestine. It is estimated that there are up to 1012 bacteria per gram of stool, belonging to 400 to 500 different species.

 

Humans benefit in many ways from their microbiome: digestive processes and detoxification processes in the intestine are supported, enzymes and vitamins are provided and colonization with harmless bacteria, for example on the skin, in the intestine, in the oral cavity and in the vagina, prevents the settlement of pathogenic bacteria.

 

However, bacteria can also cause damage to their host. This is possible if they succeed in breaking through natural barriers. If, for example, the protective layer of the skin is damaged during an injury, germs from the skin or the environment can get into deeper tissue layers and cause a wound infection. A similar situation occurs with the perforation of a hollow organ in the abdomen (“burst appendix”), in which masses of intestinal microorganisms are flushed into the sterile abdominal cavity. Since numerous types of bacteria have mechanisms that enable them to settle on artificial surfaces and organize themselves there in a so-called “biofilm”, implants inserted into the body, for example joint endoprostheses, artificial heart valves, bone-stabilizing metal plates and screws (osteosyntheses) as well as vascular catheters represent another not negligible source of infection.

Many bacteria have special pathogenic properties (virulence factors), with the help of which they at least temporarily escape the immune defence of the host organism and which enable them to spread in the host. Of great importance are toxins that destroy certain cells of the host or damage their metabolism. Thus, representatives of the pus bacterium Staphylococcus aureus are able to form an effective cell toxin that leads to tissue destruction in the skin. Some strains of the intestinal bacterium Clostridioides (Clostridium) difficile can cause severe damage to the intestinal mucosa through toxins. These dangerous bacteria occur particularly frequently when the normal intestinal flora has been permanently destroyed by unnecessary antibiotic treatments.

Agar plates Klebsiella pneumoniae
Various agar plates with the bacterium Klebsiella pneumoniae

Multidrug resistance, i.e. the atypical non-susceptibility of bacterial strains to a large number of antibiotics that would normally be effective, is not a pathogenicity factor in the literal sense, but represents a particular challenge in the treatment of bacterial infections because it has been shown that it takes longer to find an effective antibiotic and, accordingly, adequate therapy is often only initiated after a delay. Especially in regions where multidrug-resistant bacterial strains are widespread, the selection of an efficient treatment strategy can be very difficult.

 

Multidrug-resistant bacteria, which can cause serious, sometimes life-threatening infections, are becoming increasingly common, especially in hospital environments, where they can lead to disease outbreaks, often due to poor hygiene. The most important of these pathogens are summarized under the abbreviation ESKAPE, recently also ESCAPE (for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, today often replaced by Clostridioides difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.), an acronym that also indicates the ability of these microorganisms to escape antimicrobial therapy by developing effective resistance mechanisms. In the new abbreviation ESCAPE, Clostridioides difficile is considered to be an important pathogen for diarrhoeal diseases, which occur particularly after antibiotic therapies; Klebsiella and Enterobacter are summarized under their generic term Enterobacterales.

ESKAPE
Typical special media for the detection of multi-drug resistant bacteria of the "ESKAPE" group. Bacterial cultures were crossed out here in the form of their initial letters for better graphic representation. The usual procedure is shown in the picture above.

The enormous difficulties that can arise in the therapeutic management of an infection caused by multidrug-resistant pathogens prompted the World Health Organization (WHO) in February 2017 to compile a list of bacteria for the treatment of which new drugs are urgently needed. The six ESKAPE pathogens are among the germs with the highest estimated “replenishment needs”. They are also the focus of the PhagoFlow project. Whether, to what extent and when, however, the postulated development needs can be covered by research initiatives and pharmaceutical production facilities is uncertain in view of the considerable time and money involved.

  • Priority 1: critical

    • Acinetobacter baumannii, carbapenem-resistant
    • Enterobacterales (form. Enterobacteriaceae, e.g.. Escherichia coli, Klebsiella pneumoniae, Enterobacter spp.), carbapenem-resistant, 3rd generation cephalosporin-resistant
    • Pseudomonas aeruginosa, carbapenem-resistant

  • Priority 2: high

    • Campylobacter, fluoroquinolone-resistant
    • Enterococcus faecium, vancomycin-resistant
    • Helicobacter pylori, clarithromycin-resistant
    • Neisseria gonorrhoeae, 3rd generation cephalosporin-resistant, fluoroquinolone-resistant
    • Salmonella spp., fluoroquinolone-resistant
    • Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant

  • Priority 3: medium

    • Haemophilus influenzae, ampicillin-resistant
    • Shigella spp., fluoroquinolone-resistant
    • Streptococcus pneumoniae, penicillin-non-susceptible

World Health Organization (WHO): Global priority list of antibiotic-resistant bacteria to guide research, discovery and development of new antibiotics. 27.02.2017. www.who.int

Against this background, it is important to exploit existing therapeutic potential and to look for additions and alternatives to conventional treatment concepts in infection medicine. In addition to a combination of surgical measures and optimally dosed targeted antibiotic therapy tailored to the patient and his infection situation – i.e. individualized – the use of antibacterial viruses – bacteriophages – is an approach that is increasingly moving into the focus of infection treatment.