Characteristics of Antibiotic Resistance

Although microbiologists and clinicians define the resistance of pathogenic bacteria to antimicrobial agents differently, their views can be combined into a single concept: a genetically determined bacterial defense mechanism substantially increases the likelihood of unsuccessful antibiotic treatment and infection-related complications. In other words, the greater the susceptibility of a microorganism to a specific agent identified by microbiological testing, the better the expected disease outcomes. It is important to note that the clinical resistance of bacterial populations may vary depending on the site of infection or an insufficient drug dose (1).

Antibiotic resistance may be either intrinsic (e.g., characteristic of the entire cultured population of a particular bacterial species) or acquired. Examples of intrinsic resistance include the resistance of all Gram-positive microorganisms to colistin, Enterobacteriaceae spp. to glycopeptides and linezolid, and Pseudomonas aeruginosa to an extremely broad spectrum of antibiotics.

Acquired Antibiotic Resistance

A bacterium susceptible to antimicrobial agents can become resistant in two ways: through mutations in resistance-associated genes or through the incorporation of genetic material from another bacterium into its genome. Resistance-associated genes are carried by mobile genetic elements: plasmids—small, circular, double-stranded DNA molecules independent of the chromosome—or transposons (so-called jumping genes), which are DNA sequences capable of changing their position within the genome. Genetic information can be transferred in several ways (Figure 1):

• conjugation – transfer of a plasmid through a conjugation bridge between two bacteria;
• transduction – transfer of DNA by bacteriophages: part of the bacterium’s genetic material is incorporated into viruses replicating inside the bacterial cell, which, after leaving the host cell, transfer it to another bacterium;
• transformation – a bacterium takes up a free DNA strand from its surrounding environment and integrates it into its genome.

Ineffective antibiotic therapy promotes bacterial selection: susceptible microorganisms are eliminated, whereas resistant strains survive because of an insufficient treatment dose or duration, multiply, and re-establish a considerably more resistant population. This has been confirmed by studies. Analysis of individual cases has shown that resistance among urinary tract (Escherichia coli) and respiratory tract (Streptococcus pneumoniae, Haemophilus influenzae) strains may persist for up to one year after the start of antibiotic treatment, directly correlating with a broader variety of prescribed antibiotics and a prolonged course of treatment (2).

Mechanisms of Antibiotic Resistance (Figure 2)

β-Lactamases

Because bacterial enzymes hydrolyze the β-lactam ring, β-lactam antibiotics will be ineffective against a strain possessing this resistance mechanism. In addition, different types of β-lactamases have different affinities for specific classes of β-lactam antibiotics and specific responses to β-lactamase inhibitors such as clavulanic acid.

The increasingly prevalent extended-spectrum β-lactamase (ESBL)-producing enterobacterial species (e.g., E. coli, Klebsiella spp., Enterobacter spp.) make the treatment of these infections particularly difficult because these strains are resistant not only to penicillins but also to first-, second-, and third-generation cephalosporins. Of concern is the substantial increase in resistance of E. coli and Klebsiella pneumoniae to third-generation cephalosporins in the European Union between 2012 and 2015 (in many countries, more than 50% of K. pneumoniae cases were resistant). Consequently, the use of carbapenems, currently the broadest-spectrum β-lactam antibiotics developed, is increasing (Figure 3) (3).

Carbapenemases

Although carbapenems are resistant to ESBL enzymes, which cause many problems in clinical practice, their effectiveness is increasingly being reduced by the growing prevalence of carbapenemase-producing microorganisms. This enzyme group includes metallo-β-lactamases (NDM-1, VIM, and IMP) and others (KPC, OXA-48). Carbapenemases are often detected together with other resistance mechanisms, such as aminoglycoside-modifying enzymes, further complicating individualized treatment strategies.

Carbapenemase-producing Enterobacteriaceae (CPE) have become a global problem, with many southern European and developing countries recognized as endemic areas. Nearly a decade of monitoring the dynamics of CPE development by researchers in the United Kingdom (UK) revealed a highly significant frequency of these strains (Figure 4), closely associated with outbreaks of infections resistant to broad-spectrum antibiotics throughout the UK, particularly in north-west England. Nevertheless, one fact is reassuring: carbapenem-resistant E. coli and K. pneumoniae strains remain extremely rare in blood cultures. The implementation of effective infection-control practices—particularly the isolation and monitoring of patients treated in healthcare institutions abroad or in UK hospitals affected by this problem—and restrictions on carbapenem use are essential to prevent the further development of resistant bacterial groups (4).

Why Should We Be Concerned Now?

In the past, if a bacterium was resistant to one antibiotic, treatment problems could usually be resolved by prescribing another agent. Today, such a situation has become a rarity. Specialists are particularly concerned about the ESKAPE pathogens that predominate in nosocomial infections—Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, Acinetobacter baumannii, P. aeruginosa, and Enterobacter spp.—as well as other Enterobacteriaceae such as E. coli, Mycobacterium tuberculosis, and N. gonorrhoeae. Rapidly developing antibiotic resistance combined with the slow development of new agents is currently regarded as one of the most significant public health problems. The main reasons for the slow development of new-generation antimicrobial agents are:

• Antibiotic development provides limited economic benefit to pharmaceutical companies: these drugs are used in short courses, and many carry a high risk of resistance development. Because of globally applied principles of antibiotic stewardship, almost all newly developed drugs are reserved for restricted use.
• Expanded regulatory requirements increase the cost of developing new antimicrobial agents.
• The application of new methods, such as genomic technologies, in drug development has not been as successful as previously expected.

Ričardas Kundelis, MD

Lithuanian University of Health Sciences

Continued in Internistas, No. 1, 2019