Maintaining fluoroquinolone class efficacy: review of influencing factors - Perspectives - Editorial

Emerging Infectious Diseases, Jan, 2003 by W. Michael Scheld

Previous experience with antimicrobial resistance has emphasized the importance of appropriate stewardship of these pharmacotherapeutic agents. The introduction of fluoroquinolones provided potent new drugs directed primarily against gram-negative pathogens, while the newer members of this class demonstrate more activity against gram-positive species, including Streptococcus pneumoniae. Although these agents are clinically effective against a broad range of infectious agents, emergence of resistance and associated clinical failures have prompted reexamination of their use. Appropriate use revolves around two key objectives: 1) only prescribing antimicrobial therapy when it is beneficial and 2) using the agents with optimal activity against the expected pathogens. Pharmacodynamic principles and properties can be applied to achieve the latter objective when prescribing agents belonging to the fluoroquinolone class. A focused approach emphasizing "correct-spectrum" coverage may reduce development of antimicrobial resistance and maintain class efficacy.

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Development of resistance to antimicrobial agents and the emergence of multiresistant pathogens have generated worldwide concern in the medical community. Infections caused by resistant bacteria are associated with higher rates of hospitalization, greater length of hospital stay, and higher rates of illness and death (1,2). The estimated annual cost of treating infections caused by resistant bacteria in the United States is several billion dollars (3).

Antimicrobial resistance develops when bacteria are exposed to an antimicrobial agent, and selective pressure favors the growth of the resistant pathogen. To decrease selective pressure, antibacterial therapy should only be prescribed in patients with known or suspected bacterial infections. The risk for resistance can be further reduced by using an antimicrobial agent that has potent activity against the suspected pathogens at the dose and dosing frequency that maximizes its effectiveness.

Historically, several approaches to antibiotic prescribing have been employed to address antimicrobial resistance. One approach is to use a newer more potent antimicrobial in settings where resistance has emerged to an older agent. However, if newer agents are overused or used inappropriately, resistance will invariably develop to the newer drug. For example, since the late 1980s and early 1990s, ceftazidime, a third-generation cephalosporin, has been widely used against gram-negative pathogens, including Pseudomonas. However, indiscriminate use led to decreased activity against gram-negative infections and may have contributed to emergence of potent broad-spectrum [beta]-lactamases among Enterobacter, Citrobacter, Klebsiella, and other gram-negative species (4-7). Another approach to combating resistance is to continue using older agents as first-line choices, in preference to newer, more potent drags, in an effort to preserve the activity of the new drugs. The newer agents are reserved for infections caused by mutated multiresistant strains. However, as resistance continues to increase to the first-line agents, poor outcomes and secondary costs associated with clinical failures increase. By withholding the more potent agents for selected cases, these agents are increasingly compromised by the emergence of mutants selected by the less potent compounds.

An approach designed to reduce the rate at which antibiotic resistance develops is antibiotic cycling or rotation. It has been used with some success in intensive-care units (ICUs), where one class of agent has been predominantly used for a predefined period, usually 3 months, followed by use of another class for 3 months. Although not widely used, rotation has been used succesfully by Kollef et al. (8). A second approach is the use of combination therapy, whereby the additive or synergistic action of two or more drugs is exploited. Overall, resistance potential is theoretically minimized by this technique since these agents are typically from different antimicrobial classes, and different sites in the bacterial cell are targeted. Finally, a more focused approach of using the agents that demonstrate the best pharmacokinetic and pharmacodynamic profile against suspected pathogens might also reduce antimicrobial resistance. The objective of this approach is to predictably eradicate bacteria so that resistant clones are not selected.

The fluoroquinolone class of antimicrobial agents is being used empirically in an increasing number of patients because resistance has developed to the more traditional empiric agents. Fluoroquinolones are active against a wide range of multiresistant pathogens since their mode of action is against different molecular targets than other antimicrobial classes (9). Moreover, mechanisms of resistance to fluoroquinolones, apart from two unusual exceptions (10,11), are unlike almost all other class resistance mechanisms, being neither plasmid nor integron mediated.