Is It Time To Change Fluoroquinolone Breakpoints for <i>Salmonella</i> spp.?

Abstract

Fluoroquinolones are the drug of choice for treatment of invasive gastrointestinal infections in many parts of the world. Salmonella enterica is one of the most common causes of human gastroenteritis worldwide. Nontyphoidal Salmonella infections are primarily caused by consumption of contaminated foods primarily of animal origin, whereas S. enterica serovar Typhi and Paratyphi infections are spread directly or indirectly from human feces. Since the early 1990s, fluoroquinolones have in many countries been licensed for use in food production animals. The concomitant emergence and increased incidence of quinolone-resistant Salmonella strains have been an issue of intense worldwide debate. In members of the family Enterobacteriaceae, resistance to quinolones is most commonly acquired by mutations in two steps. One mutation in the gyrA gene mediates full resistance to narrow-spectrum quinolones, such as nalidixic acid and decreased susceptibility to fluoroquinolones (3, 18). A second mutation in either gyrA or gyrB genes mediates full resistance to fluoroquinolones. The current National Committee for Clinical Laboratory standards (NCCLS) breakpoint for resistance to the fluoroquinolone ciprofloxacin is ≥4 μg/ml, while the breakpoint for resistance to its veterinary equivalent, enrofloxacin, is ≥2 μg/ml (14, 15). Even though the NCCLS does not provide specific breakpoints for bacteria associated with gastrointestinal infections, the current breakpoints are widely used by clinicians, veterinarians, microbiologists, and others involved with the issues involving selection for fluoroquinolone resistance. Several studies have shown that resistance to nalidixic acid and decreased susceptibility to fluoroquinolones have increased among Salmonella spp. from food animals and infections in humans (8, 10, 13, 19-21). Some have used this as an argument against the continued usage of fluoroquinolones for food animals. Defenders of the continued usage of fluoroquinolones for food animals argue that on the basis of the NCCLS breakpoint, there is still very limited “clinical” fluoroquinolone resistance among Salmonella strains, despite several years of fluoroquinolone use in food animal production. With this letter, we do not want to get into the debate regarding the continued usage of fluoroquinolones among food animals. However, we wish to stress the importance of establishing a common breakpoint as the basis for evaluating susceptibility data and interpreting these data in a clinical context. Isolates with a single mutation in gyrA are to some extent refractory to the bactericidal effect of fluoroquinolones (2; J. D. Knudsen, R. Skov, P. Gerner-Smidt, L. V. Pallesen, and N. Frimodt-Moller, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-2091, 2001). In our opinion, there is now compelling evidence that the treatment efficacy of fluoroquinolones is reduced in humans infected with strains of Salmonella enterica that demonstrate what is regarded as decreased susceptibility to fluoroquinolones. Thus, the use of the NCCLS breakpoint at ≥4 μg/ml for ciprofloxacin may have the effect of obscuring the true occurrence of resistance to quinolones among Salmonella strains. Indeed, in several cases, decreased susceptibility to fluoroquinolones has only been detected on the basis of resistance to nalidixic acid after the patient has failed to respond to treatment with ciprofloxacin. A number of reported cases of infections with S. enterica serovar Typhi and nontyphoid Salmonella in humans are shown in Table ​Table1.1. One observation common to all reports is that fluoroquinolones were ineffective in treating patients who were infected with isolates for which the MICs of fluoroquinolones were between 0.06 and 2 mg/liter. In five case reports on nontyphoid Salmonella infections, resistance to nalidixic acid and decreased susceptibility to ciprofloxacin (MIC, 0.125 to 2 mg/liter) developed during therapy. Helms et al. (7) reported that patients infected with isolates for which MICs were between 0.06 and 0.38 mg/liter were five times more likely to die within 2 years after infection than patients infected with isolates for which MICs were lower. In the latter report, all isolates were isolated before initial therapy, and it is highly probable that the patients were originally infected with isolates with decreased susceptibility to fluoroquinolones. TABLE 1. Different studies reporting treatment failures in patients infected with Salmonella enterica serovar Typhi and non-Typhi Salmonella isolates with decreased susceptibility to fluoroquinolones In conclusion, the available literature has demonstrated that when patients are infected with Salmonella isolates with decreased susceptibility to fluoroquinolones, treatment failures may occur. Thus, to reduce the risk for humans, we recommend that for Salmonella, a breakpoint of ≥0.125 μg/ml for fluoroquinolones should be used when evaluating both laboratory sensitivity tests and for the surveillance of resistance to this important group of antimicrobials in both human and veterinary medicine. The most optimal solution may be to use testing for susceptibility to nalidixic acid as a screening tool and then determine the MIC of ciprofloxacin for all nalidixic acid-resistant isolates. An artificially high breakpoint not only may lead to the wrong clinical decisions, but can also obscure surveillance data. And if the surveillance data are flawed, it is impossible to develop and improve policies for prudent drug use in both food production and human medicine.