Abstract
We present the results of a longitudinal surveillance study (1995–2014) on fluoroquinolone resistance (FQ-R) among Belgian non-invasive Streptococcus pneumoniae isolates (n = 5,602). For many years, the switch to respiratory fluoroquinolones for the treatment of (a)typical pneumonia had no impact on FQ-R levels. However, since 2011 we observed a significant decrease in susceptibility towards ciprofloxacin, ofloxacin and levofloxacin with peaks of 9.0%, 6.6% and 3.1% resistant isolates, respectively. Resistance to moxifloxacin arised sporadically, and remained <1% throughout the entire study period. We observed classical topoisomerase mutations in gyrA (n = 25), parC (n = 46) and parE (n = 3) in varying combinations, arguing against clonal expansion of FQ-R. The impact of recombination with co-habiting commensal streptococci on FQ-R remains marginal (10.4%). Notably, we observed that a rare combination of DNA Gyrase mutations (GyrA_S81L/GyrB_P454S) suffices for high-level moxifloxacin resistance, contrasting current model. Interestingly, 85/422 pneumococcal strains display MICCIP values which were lowered by at least four dilutions by reserpine, pointing at involvement of efflux pumps in FQ-R. In contrast to susceptible strains, isolates resistant to ciprofloxacin significantly overexpressed the ABC pump PatAB in comparison to reference strain S. pneumoniae ATCC 49619, but this could only be linked to disruptive terminator mutations in a fraction of these. Conversely, no difference in expression of the Major Facilitator PmrA, unaffected by reserpine, was noted between susceptible and resistant S. pneumoniae strains. Finally, we observed that four isolates displayed intermediate to high-level ciprofloxacin resistance without any known molecular resistance mechanism. Focusing future molecular studies on these isolates, which are also commonly found in other studies, might greatly assist in the battle against rising pneumococcal drug resistance.
Highlights
Streptococcus pneumoniae is a major cause of community-acquired respiratory infections including otitis media and pneumonia, as well of serious invasive infections like septicaemia and meningitis [1]
Since the global switch to LVX and MXF was established, the worldwide prevalence of fluoroquinolone resistance (FQ-R) in S. pneumoniae remained below 2% [7] it seems unrelated to the serotype switches that were observed upon the introduction of 7- and 13-valent pneumococcal conjugate vaccination [8]
A total of 5,602 unduplicated clinical isolates of S. pneumoniae were included in this study
Summary
Streptococcus pneumoniae is a major cause of community-acquired respiratory infections including otitis media and pneumonia, as well of serious invasive infections like septicaemia and meningitis [1]. Penicillins and macrolides were mainstay in the treatment of respiratory diseases for decades [2], but the worldwide spread of drug-resistant clones translated into increased usage of fluoroquinolones [3,4]. The early fluoroquinolones ciprofloxacin (CIP) and ofloxacin (OFL) target ParC and display poor potency against pneumococci, rapidly leading to emergence of resistance [6]. In the late 1990s, they were replaced by the so-called “respiratory fluoroquinolones levofloxacin (LVX; the active isomer of ofloxacin) and moxifloxacin (MXF) that acts on both enzymes [2]. Since the global switch to LVX and MXF was established, the worldwide prevalence of fluoroquinolone resistance (FQ-R) in S. pneumoniae remained below 2% [7] it seems unrelated to the serotype switches that were observed upon the introduction of 7- and 13-valent pneumococcal conjugate vaccination [8]
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