Control of Fluoroquinolone Resistance through Successful Regulation, Australia

Medscape CME Activity

Usefulness of Fluoroquinolones

Contribution of Fluoroquinolone Use to Fluoroquinolone Resistance

Low Use of Quinolone by Humans and Prohibition of Its Use in Food-producing Animals in Australia

Low Resistance Rates in Australia Compared with Other Countries

Conclusions

Acknowledgment

References

Figure 1

Figure 2

Table 1

Table 2

Suggested Citation

Allen C. Cheng, John Turnidge, Peter Collignon, David Looke, Mary Barton, and Thomas Gottlieb

Author affiliations: Monash University, Melbourne, Victoria, Australia (A.C. Cheng); Alfred Hospital, Melbourne (A.C. Cheng); Women’s and Children’s Hospital, Adelaide, South Australia, Australia (J. Turnidge); University of Adelaide, Adelaide (J. Turnidge); The Canberra Hospital, Garran, Canberra, Australia (P. Collignon); Australian National University, Canberra (P. Collignon); Princess Alexandra Hospital, Brisbane, Queensland, Australia (D. Looke); University of Queensland, Brisbane (D. Looke); University of South Australia, Adelaide (M. Barton); Concord Hospital, Sydney, New South Wales, Australia (T. Gottlieb); and University of Sydney, Sydney (T. Gottlieb)

Abstract

Fluoroquinolone antimicrobial drugs are highly bioavailable, broad-spectrum agents with activity against gram-negative pathogens, especially those resistant to other classes of antimicrobial drugs. Australia has restricted the use of quinolones in humans through its national pharmaceutical subsidy scheme; and, through regulation, has not permitted the use of quinolones in food-producing animals. As a consequence, resistance to fluoroquinolones in the community has been slow to emerge and has remained at low levels in key pathogens, such as Escherichia coli. In contrast to policies in most other countries, this policy has successfully preserved the utility of this class of antimicrobial drugs for treatment of most infections.

Nalidixic acid, the first quinolone introduced into clinical practice, was developed in the 1960s; its use was largely confined to the treatment of urinary tract infections. After the development of several fluoroquinolone antimicrobial drugs, including ciprofloxacin and norfloxacin in the 1980s, and then ofloxacin and levofloxacin, and more recently gatifloxacin and moxifloxacin, the use of this class of antimicrobial drugs increased greatly worldwide. Estimates from the late 1990s suggested that quinolones were the most prescribed antibacterial agent worldwide (1). Soon after these drugs were registered, the government of Australia developed policies to restrict use of quinolone antimicrobial drugs by humans and to prevent their use in food-producing animals. These policies have been associated with low rates of resistance to this valuable antimicrobial drug class in Australia.

Usefulness of Fluoroquinolones

Quinolone antimicrobial drugs are commonly used as first-line empiric therapy for urinary tract infections, upper and lower respiratory tract infections, enteric infections, and gonococcal infection. They are particularly useful against deep infections caused by gram-negative bacteria, including those, such as Pseudomonas spp., that are resistant to other orally administered antimicrobial drugs. Specific quinolone antimicrobial drugs administered to pets and food-producing animals are known to transmit cross-resistance to humans (1).

Contribution of Fluoroquinolone Use to Fluoroquinolone Resistance

Quinolones act by inhibiting bacterial DNA gyrase and/or topoisomerase IV (2). Target modification is a common mechanism for resistance, in which >1 point mutations in the gyrA or parC genes generate unequivocal resistance. This mutation can be induced in vitro by exposure to antimicrobial drug concentrations of >8× the MIC (3). Other mechanisms can also mediate resistance, including decreased expression of porins, leading to decreased membrane permeability, and overexpression of antimicrobial drug efflux pumps (2). The transfer of quinolone resistance by mobile genetic elements has the potential to rapidly disseminate resistance, and its contribution to the spread of resistance is being increasingly recognized (4). Under certain circumstances, resistance to fluoroquinolones can emerge during treatment. Some studies have reported that < 50% of all patients taking quinolones for prostatitis are colonized with quinolone-resistant Escherichia coli strains (5) and have described quinolone resistance after treatment courses of as few as 3 days (6). Whether resistance is caused by de novo resistance mutations or amplification of resistant strains already present in low numbers is not known. Furthermore, even parenteral fluoroquinolones are actively excreted into the intestine and may select for resistance in normal intestinal flora.
Although other factors are likely to contribute to resistance in persons, ecologic data show an association between fluoroquinolone use and resistance. This finding is supported by differences between the usual habitats of certain bacterial species and the effect fluoroquinolone use has on resistance development. Because some bacteria, such as Streptococcus pneumoniae, Neisseria gonorrhoeae, and Salmonella enterica serovar Typhi are transmitted from human to human, resistance in these organisms is likely to indicate human use of antimicrobial drugs and consequent antimicrobial drug selection pressure. Resistance in N. gonorrhoeae and S. Typhi are also influenced by variations in global epidemiology of disease and in ease of availability of quinolone antimicrobial drugs, including over-the-counter access in Asia, where much higher levels of resistance have been documented (7). Resistance in Campylobacter spp. and non-typhoidal salmonella is more likely to reflect antimicrobial drug administration to food-producing animals (8). E. coli is widely distributed among humans, animals, water, and some foods; thus, selection pressure is likely to be exerted by antimicrobial drug use in human and agricultural sectors. This likelihood is supported by molecular typing studies in which researchers examined E. coli strains resistant to trimethoprim-sulfamethoxazole, quinolones, and extended-spectrum cephalosporins in humans and in commercial poultry products in the United States, where these antimicrobial drugs are or have been used in poultry production (9). The authors found that resistant strains in humans were more closely aligned with resistant isolates in poultry than to susceptible human strains, suggesting that the resistant strains in humans were most likely to be of poultry origin.

Low Use of Quinolone by Humans and Prohibition of Its Use in Food-producing Animals in Australia

Three quinolones are available for systemic use in humans in Australia: norfloxacin, ciprofloxacin, and moxifloxacin. Other quinolones have been available in the past (nalidixic acid, enoxacin, trovafloxacin, and gatifloxacin) but have been withdrawn from the market for a variety of reasons. In Australia, national guidelines for antimicrobial drug use in humans have been published and expanded since 1976. Indications for antimicrobial use are reviewed by a panel of infectious diseases experts approximately every 3 years (10). These guidelines are widely promulgated and generally accepted as a standard for prescribing antimicrobial drugs in the community and in hospitals.
The use of quinolone antimicrobial drugs in Australia has been actively constrained by guidelines that recognize their status as a reserve antimicrobial drug. For example, in the current guidelines, ciprofloxacin is not listed as an option in the management of lower urinary tract infection, and it is listed as a treatment for acute pyelonephritis only when resistance to all other recommended drugs is proven or the causative organism is Pseudomonas aeruginosa. For treatment of foot infections in persons with diabetes, ciprofloxacin is only recommended as an alternative for patients with penicillin hypersensitivity; the drug is listed for water-related infections caused by Aeromonas spp., but is not listed for treatment of wounds caused by other organisms. For respiratory infections, moxifloxacin is not listed as an option for the empiric treatment of community-acquired pneumonia in outpatients, except in patients who have severe penicillin hypersensitivity; ciprofloxacin is listed as an option to treat Legionella infection and in directed therapy for infections in which a susceptible pathogen has been identified. In almost all other countries, quinolones have been freely available and used for a broad range of indications as first-line therapy and have been promoted in treatment guidelines for conditions such as community-acquired pneumonia and uncomplicated urinary tract infections (11,12)

Australia has a subsidized outpatient pharmaceutical plan, the Pharmaceutical Benefits Scheme (PBS). Relatively expensive drugs (more than AU$30, in 2010 dollars) are not used widely unless prescribed by doctors according to indications listed by PBS. After 1988, ciprofloxacin use was subsidized by the PBS for “serious infections for which no other oral antimicrobial agent is appropriate.” In response to growing expenditures in the early 1990s, the Pharmaceutical Benefits Advisory Committee consulted with the National Health and Medical Research Council Working Party on Antibiotics, which suggested that specific indications would result in a more targeted use of quinolones. This suggestion was subsequently adopted by the PBS, and the list of indications underwent several modifications over the years, eventually leading to the PBS authority indications listed in Table 1.