Factors influencing fluoroquinolone resistance - Letters - Letter to the Editor

Emerging Infectious Diseases, Dec, 2003 by Daniel F. Sahm, Clyde Thornsberry, Mark E. Jones, James A. Karlowsky

Levofloxacin, gatifloxacin, and moxifloxacin all have susceptibility rates >99% for S. pneumoniae (22,23). Although resistance is rare, considerable cross-resistance among fluoroquinolones is observed once two or more key mutations (e.g., Ser (79) in ParC, Ser (81) in GyrA) are detected (24,25). Using topoisomerase IV-selecting fluoroquinolones (ciprofloxacin and levofloxacin) in the same patient population as DNA gyrase-selecting fluoroquinolones (gatifloxacin and moxifloxacin) could potentially accelerate the development of double mutants (ParC and GyrA) and clinically important class resistance because selective pressure would be applied to both enzyme targets (26).

The review stated that, since 1999, at least 20 case reports of pulmonary infection that did not respond to levofloxacin therapy have been published. This number is remarkably small considering that >250 million patients have been treated with levofloxacin worldwide. A number of the treatment failures cited had documentation of prior ciprofloxacin use and ciprofloxacin failure, and many isolates were not tested for levofloxacin susceptibility before treatment (27). We agree with the recommendation in the cited Davidson et al. reference: a patient's failure to respond to one fluoroquinolone is sufficient reason not to use other fluoroquinolones (27). Isolated clinical failures will occur with the use of any antimicrobial agent when treating pneumococcal pneumonia.

The notion that fluoroquinolone therapy can be "targeted" for an indication requires challenge as fluoroquinolone therapy will always result in systemic drug levels. Evidence does not indicate that the use of two fluoroquinolones, such as ciprofloxacin and moxifloxacin, minimizes fluoroquinolone resistance. Targeted fluoroquinolone therapy may in fact have adverse implications for the patient and for overall institutional resistance patterns. For example, the use of ciprofloxacin for urinary tract infections exposes resident streptococci in the respiratory tract to an agent that has demonstrated weaker activity against pneumococci, thus potentially selecting for pneumococcal resistance (9). Moreover, 20%-35% of ciprofloxacin is excreted through the intestinal tract (Cipro package insert), compared to 4% of levofloxacin (Levaquin package insert). Studies have shown that ciprofloxacin displays weaker in vitro activity (lower percentage of isolates susceptible) than levofloxacin for several gram-negative enteric bacteria (2,3). Stepwise adaptive changes towards fluoroquinolone resistance in enteric bacteria may be selected by fluoroquinolones with weaker in vitro activity and higher levels of exposure in the intestinal tract. Therefore, ciprofloxacin would have a greater potential than levofloxacin for the selection of resistant strains of intestinal gram-negative pathogens. A recent report stated that ciprofloxacin-resistant Escherichia coli were isolated from the feces of 48% of patients treated with ciprofloxacin for prostatitis; before ciprofloxacin therapy, only ciprofloxacin-susceptible E. coli were isolated from the feces of these patients (28). Further, given that 25% of moxifloxacin is excreted through the intestinal tract (Avelox package insert), the use of moxifloxacin for respiratory infections exposes bacteria in the intestinal tract to a fluoroquinolone with greater activity against Bacteroides fragilis and other intestinal anaerobes than levofloxacin (29,30). Moxifloxacin has a greater potential than other fluoroquinolones to alter the normal intestinal flora and select for vancomycin-resistant enterococci (31) and intestinal gram-negative strains with increased fluoroquinolone resistance.