March 01, 2011
The rising rate of fluoroquinolone resistance is a serious cause of concern for both human and animal medicine. The discovery and subsequent knowledge of plasmid-mediated quinolone resistance (PMQR) has uncovered a new and more dangerous resistance mechanism that allows bacteria to adapt and survive in the face of clinical concentrations of fluoroquinolones. Part one of this two-part series explored the history and mechanisms behind the development of fluoroquinolone resistance. Part two will address the clinical importance and implications of PMQR and conclude with strategies to address this issue.
CLINICAL IMPORTANCE
As mentioned, PMQR confers only low-level resistance (MIC 0.125 g/ml)–not enough to qualify as resistant (MIC 4 g/ml) according to the current Clinical and Laboratory Standards Institute (CLSI) breakpoint criteria for quinolone resistance. With such low MICs, these isolates, despite carrying mutations that confer decreased quinolone susceptibility, will be classified as susceptible (MIC 1 g/ml), meaning that clinicians can still prescribe and thus expose them to fluoroquinolones and quinolones.
This is problematic because PMQR enables these susceptible organisms to survive even at therapeutic dosage levels and then readily circulate their genes. The continued exposure to these antibiotic agents leads to an increased selection for plasmid-carrying pathogens, which then rapidly leads to the overall development of high-level clinically significant levels of resistance.
That low resistance levels conferred by PMRQ can still lead to therapeutic failure while going undetected using the current CLSI criteria raises the question of whether it is safe to prescribe fluoroquinolones to treat PMRQ gene-bearing organisms even though they do not qualify as resistant. It also raises the question of whether clinical breakpoints should be revised in the case of plasmid-bearing pathogens.
Additionally there is a strong association between resistance to quinolones and resistance to other antibiotics, particularly broad spectrum B-lactamases and aminoglycosides. This indicates that organisms with plasmids carrying a quinolone resistant gene increase the likelihood of the development of multi-drug resistant bacteria, as the prescription of a quinolone may not only select for quinolone resistance but also select for resistance to other classes of drugs.
The discovery of plasmid-mediated resistance genes in some non-Typhi serotypes of Salmonella enterica (NTS) in animals has also raised a major public health concern. The presence of these resistance genes in NTS suggests the worrisome potential of horizontal transfer (and thus spread) of resistance genes between animal and infection-causing human pathogens through the food supply.
WHAT S NEXT
The extensive use and misuse of quinolones and fluoroquinolones is a major driver of the resistance and is playing a large role in the continuous rise in the prevalence of quinolone-resistant isolates, both in clinical and veterinary medicine. Efforts to promote their judicious use are therefore essential for their preservation. Some strategies that have been implemented in different parts of the world include prohibiting their use in food animals such as poultry, restricting the use of fluoroquinolones in agriculture to only therapeutic use, developing antibiotic stewardship programs in hospitals that control the use of fluoroquinolones through drug rotation, cycling and restriction, and carrying out education campaigns targeting physicians, patients, and the community to create awareness of inappropriate use of antibiotics.
Additionally, a re-evaluation of CLSI quinolone and fluoroquinolone breakpoints must be pursued in the context of the new mechanism, PMQR. The current breakpoints allow for quinolone treatment to continue, as organisms carrying these plasmid-mediated resistance genes go undetected, resulting in further dissemination of these plasmids thanks to the selection pressure. Lowering the clinical breakpoints will help clinicians detect the low-level resistance phenotype conferred by these genes and avoid prescribing quinolones as treatment.
The loss of the efficacy of such a potent and wide-spectrum class of antimicrobials to resistance is not good news in both human and veterinary medicine. Resistance to fluoroquinolones increases hospitalizations, lengthens hospital stays, and may lead to further complications in treatment. In cases such as complicated Salmonella infections in humans, fluoroquinolones are the only available drugs, making resistance to fluoroquinolones a fatal threat. Additionally the advent of the PMQR mechanism points to the increased risk of spreading resistance not just to fluoroquinolones, but also to other important antimicrobial classes due to co- transmission. Addressing this issue through judicious use of antimicrobials and re-assessment of clinical breakpoints will be an important step in the preservation of the effectiveness of this important drug class.
This post is part of a larger series exploring trends in CDDEP’s ResistanceMap. To view the full series, click on the ‘ResistanceMap’ tag below.
Image credit: Flickr: selva
