Fluoroquinolone-Resistant Pneumococci: Maybe Resistance Isn't Futile?

By 2000, the emergence of fluoroquinolone-resistant pneumococci in North America seemed imminent. The prevalence of fluoroquinolone nonsusceptibility, although <1% worldwide, was high in many countries, including Spain (7%), Hong Kong (14.3%), South Korea (2.9%), Sri Lanka (9.5%), The Philippines (9.1%), and South Korea (6.5%) [1–5]. In Canada, Chen et al. [6] found that the overall prevalence of ciprofloxacin-resistant pneumococci (MIC, ⩾4 µg/mL) had increased from 0% in 1993 to 1.7% in 1997–1998 (P = .01). In adults, the prevalence increased from 1.5% to 2.9%. Linares et al. [7] reported an increase in the prevalence of ciprofloxacin-resistant pneumococci from 0.9% in 1991–1992 to 3% in 1997–1998 in Spain. In Hong Kong, Ho et al. [8] documented an increase in the prevalence of levofloxacin-nonsusceptible isolates (MIC, ⩾4 µg/mL) from 5.5% in 1998 to 13.3% in 2000. However, despite these ominous figures from many countries, the prevalence of resistance in pneumococci in North America has remained low [9–11], and in one report, it has even been found to have decreased [12]. In this issue of Clinical Infectious Diseases, Richter et al. [9] present the results of susceptibility tests of 1902 Streptococcus pneumoniae isolates collected in the United States during the period of 2001–2002. Although there was a 2-fold increase in the prevalence of ciprofloxacin resistance (from 1.2% to 2.7%) and levofloxacin nonsusceptibility (from 0.6% to 1.3%), overall rates of resistance were still low. Powis et al. [10] reported almost identical results from a cross-Canada study, with overall rates remaining low despite a 2-fold increase in the prevalence of ciprofloxacin resistance (from 1.4% in 2000 to 2.7% in 2002) and levofloxacin nonsusceptibility (from 1.0% to 2.2%). A recent US surveillance study performed in 2002 by Karlowsky et al. [11] continues to report rates of levofloxacin nonsusceptibility of <1%. Pletz et al. [12] even found a decrease in resistance rates when they reported the characterization of all invasive levofloxacin-resistant S. pneumoniae isolates (n = 50) obtained from the Centers for Disease Control and Prevention's multistate Active Bacterial Core Surveillance (ABCS) program from 1998 to 2002. The prevalence of resistance among all isolates increased from 0.1% in 1998 to 0.6% in 2001 (P = .008) but decreased to 0.4% in 2002. Two events have occurred since 2000 that may have reduced the selective pressures that drive fluoroquinolone resistance in North America: the introduction of more-potent respiratory fluoroquinolones, and the introduction of pneumococcal conjugate vaccine (PCV). One of the drivers of fluoroquinolone resistance in pneumococci is the use of fluoroquinolones with marginal pneumococcal activity for the treatment of respiratory tract infections. Ciprofloxacin, which was introduced in 1987, a decade before the “respiratory fluoroquinolones,” was approved and promoted for the treatment of infections due to S. pneumoniae. However, subsequent studies found that its use for pneumococcal infections was associated with poor eradication rates for both acute exacerbations of chronic bronchitis and pneumonia. Reports of the development of resistance in association with its increasing use soon followed [6]. Resistance to quinolone antimicrobials in S. pneumoniae can result from spontaneous target mutations in the quinolone resistance—determining regions of genes encoding subunits of topoisomerase IV (primarily parC) or DNA gyrase (primarily gyrA)—so called “de novo” resistance. Knowing what we now know about pharmacokinetic/pharmacodynamic parameters, it is not surprising that this occurred. Various studies have shown that the ratio of the area under the curve (AUC) to the MIC is predictive of efficacy and that the ratio most predictive of bacterial eradication and clinical success for pneumococci is >30 [13]. For fully susceptible pneumococci, the ciprofloxacin AUC/MIC ratio is only 21, whereas the “respiratory fluoroquinolones,” including levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin, have AUC/MIC ratios in excess of this value (table 1). In vitro and in vivo studies suggest that the greater the pneumococcal activity of the fluoroquinolone, the less likely it is that it will enrich resistant bacterial subpopulations [14, 15]. Evidence from other organisms supports the finding that pharmacokinetic/pharmacodynamic parameters may indeed have played a role in the promotion and prevention of the emergence of fluoroquinolone resistance in S. pneumoniae. The fluoroquinolones that have AUC/MIC ratios well in excess of 100 for both Haemophilus influenzae and Moraxella catarrhalis have been used for more than a decade for the treatment of patients with acute exacerbations of chronic bronchitis who are infected or colonized with these organisms, yet reports of resistance are rare. On the other hand, the use of a low dose of ciprofloxacin for the treatment of Neisseria gonorrhoeae in Asia has been responsible for the evolution and dissemination of quinolone resistance to this organism. Pharmacokinetics and pharmacodynamics of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. The heptavalent PCV, which was licensed in the United States in February 2000 and in Canada in June 2001, includes those pneumococcal serotypes that most commonly cause invasive and antibiotic-nonsusceptible disease in young children. The ABCS program found that, only 2 years after PCV introduction, the incidence of infection due to penicillin-nonsusceptible pneumococcal strains diminished by 35% [16]; this presumably resulted from the interruption of the transmission of antibiotic-resistant strains by a blocking of the acquisition of vaccine-serotype pneumococci that are resistant to antibiotics. Talbot et al. [17] evaluated the effects of the introduction of PCV on the epidemiology of cases of antibiotic-nonsusceptible invasive pneumococcal disease from January 1995 through December 2002 identified through active surveillance in 5 Tennessee counties. The proportion of penicillin-nonsusceptible invasive pneumococcal isolates among children aged <2 years decreased from 59.8% in 1999 to 30.4% in 2002 (P < .01). After 2001, similar decreases in the proportion of penicillin-nonsusceptible isolates recovered were seen among persons aged ⩾2 years. Decreases in the proportion of fluoroquinolone-nonsusceptible isolates may also be related to the introduction of PCV. Before 2000, the conventional wisdom was that fluoroquinolone resistance was the result of the development of de novo mutations in unrelated susceptible pneumococci exposed to these drugs [6]. However, since then, there has been growing evidence supporting clonal dissemination as a mechanism for increasing fluoroquinolone resistance, as evidenced by the detection of fluoroquinolone-resistant international clones [18]. Richter et al. [9] found that 44 (40%) of the levofloxacin-nonsusceptible pneumococci isolates belonged to 8 molecular types closely related to a widespread clone (Spain23F-1 [19 isolates], Spain9V-3 [9 isolates], Spain6B-2 [5 isolates], Taiwan19F-14 [5 isolates], Tennessee23F-4 [3 isolates], England14–9 [1 isolate], Greece6B-22 [1 isolate], and Tennessee14–18 [1 isolate]). More importantly, the serotypes included in the heptavalent PCV (4, 6B, 9V, 14, 18C, 19F, and 23F) accounted for 53% of the 44 levofloxacin-nonsusceptible isolates. In the report by Pletz et al. [12], it was found that the reduction in the number of vaccine serotypes that were fluoroquinolone resistant could account for the reduction in fluoroquinolone resistance in 2002. Only 22% of resistant isolates were not covered by the conjugate vaccine serogroups. Perhaps the continued use of potent fluoroquinolones and PCV will minimize the emergence of fluoroquinolone resistance, thereby preserving this class of antimicrobials for this important pathogen. Maybe resistance is not futile. Potential conflicts of interest. D.E.L. has received recent research funding from Bayer, Bristol-Myers Squibb, and GlaxoSmithKline.

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