Quinolones and the Clinical Laboratory

In the United States, nine fluoroquinolones are currently approved for human use. Norfloxacin was the first fluoroquinolone approved for human use (1986), followed by ciprofloxacin (1987), ofloxacin (1990), enoxacin (1991), lomefloxacin (1992), levofloxacin (1996), trovafloxacin (1997), gatifloxacin (1999), and moxifloxacin (1999). Gemifloxacin is currently undergoing clinical investigation in the United States.

As a class, the newer fluoroquinolones possess many characteristics that make them useful antimicrobial agents, including a broad spectrum of activity against Gram-negative and gram-positive organisms, good oral absorption and tissue penetration, relatively long serum elimination half-lives that allow once or twice daily dosing, predictable drug-drug interactions, and a relatively low incidence of serious side effects. However, not all fluoroquinolones show all of these characteristics. In addition, several of the fluoroquinolones continue to be expensive alternatives to other regimens.

1. Resistance to quinolones limits drug selection for treatment of many infections.
2. Organisms resistant to quinolones often are resistant to other classes of antimicrobials.
3. Quinolones are frequently prescribed before culture results are known. Prompt reporting of resistance reduces the risk of complications of illnesses caused by inadvertent treatment of resistant organisms.
4. Reporting susceptibilities to various quinolones provides the information necessary to choose an appropriate therapy that will minimize the selection of mutations leading to resistance.

Quinolones inhibit two enzymes that are required for bacterial DNA synthesis, i.e., DNA gyrase and topoisomerase IV. Resistance to quinolones occurs through chromosomal mutations in the genes encoding these enzymes and by porin and efflux mutations. The enzyme mutations result in an alteration of the target region where the drug binds to the enzyme; the drug exhibits reduced affinity for the target site and becomes ineffective. Mutations that result in alterations of the outer membrane porin proteins of Gram-negative organisms lead to decreased permeability of the drug through the outer membrane so less drug reaches the target enzyme. Mutations that enhance the organism’s efflux capability increase the amount of drug pumped out of the cell. The enzyme target site, porin, and efflux mutations may result from the selective pressure of exposure of the organism to antimicrobial agents during therapy and may cause treatment failure.

The number and location of mutations affecting critical sites determine the level of resistance. Organisms may have alterations in more than one enzyme target site and, in Gram-negative organisms, may contain more than one porin change. Many resistant organisms have multiple enzyme target site, porin, and efflux mutations, producing high-level resistance to quinolones. In contrast, organisms with decreased susceptibility produced only by porin changes usually have lower minimum inhibitory concentrations (MICs).

Yes. The fluoroquinolone susceptibility profile for each clinical isolate is determined by the number and location of mutational changes in specific enzyme target sites, porin proteins, and efflux mechanisms. The effect of each mutation in an isolate is not equivalent for all fluoroquinolones, due to variations of the chemical structures among this class of agents. Therefore, an organism with one or more mutations may have resistant MICs/zone sizes to one quinolone but have intermediate or susceptible MICs/zone sizes to another quinolone.

During therapy, the potential exists for an organism with a single mutation to acquire a second mutation, leading to high-level resistance. After multiple mutations occur, an organism is generally highly resistant to all quinolones.

Resistance to quinolones has been reported in a variety of important bacterial pathogens, including Escherichia coli, Klebsiella pneumoniae, and other enteric organisms; Pseudomonas aeruginosa; Chlamydia trachomatis and Mycoplasma pneumoniae; Campylobacter jejuni; Burkholderia cepacia; Stenotrophomonas maltophilia; Neisseria gonorrhoeae; Staphylococcus aureus (especially oxacillin-resistant strains); Enterococcus faecium; and Streptococcus pneumoniae.