February 22, 2011
The effectiveness and broad-spectrum activity of fluoroquinolones have made this antibacterial class one of the most widely used, both in human medicine and veterinary practice. In fact, the fluoroquinolone ciprofloxacin is the most heavily consumed antibacterial agent worldwide. Fluoroquinolones have been used to treat and prevent infections caused by Salmonella enterica, Campylobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Neisseria gonorrhoeae and Streptococcus pneumoniae. In veterinary practice, fluoroquinolones are also very extensively used for both therapeutic and non-therapeutic purposes.
The widespread use of fluoroquinolones has contributed to the rapid emergence of resistance worldwide. As we see from ResistanceMap, In the United States, fluoroquinolone resistance has increased significantly over the past decade, exceeding 25% resistance in outpatient E. coli samples in some areas. The resistance rate to either ciprofloxacin or to levofloxacin increased from 2.8% (1998 2003) to 11.8% (2004 2007) in clinical isolates in Taiwan and about 25% of healthy individuals living in Barcelona were found to be intestinally colonized with quinolone-resistant E. coli.
This post will explore the mechanisms behind the development of fluoroquinolone resistance.
HISTORY
The first quinolone, nalidixic acid a by-product of the synthesis of the antimalarial compound chloroquine was introduced in 1962. However this quinolone and other derivatives that followed exhibited a narrow spectrum of activity, and were used only for the treatment of urinary tract infections (UTIs). In the 1980s the addition of a fluorine atom on the quinolone molecule yielded ciproflaxin, the first fluoroquinolone. This compound was found to be more potent against Enterobacteriaceae (gram-negative pathogens), exhibiting a wider spectrum of activity beyond UTIs. Since the 1980s, newer compounds of these families have been developed that have shown bactericidal activities against both gram-negative and gram-positive pathogens.
Unlike the prior antimicrobial agents, quinolones and fluoroquinolones had two seemingly unbeatable advantages over Enterobacteriaceae.
First, these antimicrobials were fully synthetic, meaning that upon introduction there were no pre-existing resistance genes to this class in nature that the bacteria could easily acquire. Thus, the development of resistance would be significantly delayed. Second, in order for the bacteria to be able to acquire and pass on clinically significant fluoroquinolone levels of resistance, a rare genetic event of two (or more) simultaneous mutations would have to take place within the same cell.
However a little over 20 years since the introduction of fluoroquinolones, reports of quinolone and fluoroquinolone resistance have now become common and widespread. Interestingly, the resistance is rising independently, numerous times, in organisms that are fully susceptible. The frequency and ease with which this resistance emerged and spread challenged what was traditionally understood about the mechanisms of fluoroquinolone resistance, and led to the 1998 discovery of plasmid-mediated quinolone resistance (PMQR).
MECHANISMS OF RESISTANCE
Prior to 1998, there were two main recognized mechanisms of fluoroquinolone resistance. In the first mechanism, bacteria develop mutations that alter the quinolone-binding site on two target enzymes DNA gyrase and topoisomerase IV. Alterations of the fluoroquinolone-binding site, which happen through amino-acid substitutions on the binding surface, diminish the binding ability and thus bactericidal function of the antibiotic.
In the second mechanism, bacteria experience mutations that decrease fluoroquinolone accumulation inside the bacterial cell. These mutations either decrease the bacterial cell s outer membrane permeability, which limits fluoroquinolone entry, or increase the activity of the efflux pumps, which helps to extrude quinolones that do gain access to the cytoplasmic membrane.
Both of these mechanisms are chromosomal mutational and thus spread their resistance vertically (mutations arise in an individual organism and are passed on to their progeny).
The discovery of quinolone-resistance-encoding genes on plasmids introduced a third understanding of the transferability of resistance that accounted for the frequency and ease with which fluoroquinolone resistance occurs. This mechanism, PMQR, relies on plasmids (not chromosomes), which transfer resistance genes horizontally, between different bacterial strains. Horizontal gene transfer is worrying–not only is it faster than vertical gene transfer but this transfer can happen between two genetically unrelated bacteria strains with different resistance genes, increasing the rate at which multi-drug resistance occurs.
What we see with the emergence of fluoroquinolone-resistance is that chromosomal- and plasmid-based resistance mechanisms can work together to accelerate the development of high resistance levels. Plasmids with quinolone-resistant gene elements lead to low-level fluoroquinolone resistance and facilitate the selection of the chromosomal quinolone mutations, which then leads to higher-level quinolone resistance when faced with selection pressure. Strains carrying plasmids conferring low-level resistance have been found to be 100 times more likely to give rise to spontaneous resistant mutants than a plasmid-free strain.
What does this mean in the context of human and animal health? Are these findings cause for public health concern, and if so, what needs to be done to address this new resistance mechanism? Part 2 will explore the clinical importance and implications of PMQR. Additionally it will suggest some possible strategies to curb the dissemination of these plasmid determinants.
This post is the first in a larger series exploring trends in CDDEP’s ResistanceMap. To view the full series, click on the ‘ResistanceMap’ tag.
