F N H C 3 O O N H N Figure 2 Moxiﬂoxacin molecule.. Fukuda et al 2001). Topoisomerase IV was identiﬁed as the preferential target, with puriﬁed S. aureus DNA gyrase and topoisomerase IV enzymes by Ince and colleagues (Ince et al 2003). Griggs and co-workers (Griggs et al 2003) selected mutants with preferred afﬁnity for DNA gyrase. Exposure to ﬂuoroquinolones may select single step mutants and or bacterial populations with increased tolerance or resistance. Mechanisms of resistance to the ﬂuoroquinolones include subpopulations (mutants) with 1) mutations in DNA gyrase and or topoisomerase genes that alter/reduce the binding afﬁnity of the enzymes, 2) gene mutations that block drug entry, 3) presence of an efﬂux pump that reduces drug accumulation and 4) unique genes that confer speciﬁc resistance against S. aureus (Zhanel et al 2002; Wise 2003; Mah 2004; Jacoby 2005; Van Bambeke et al 2005). Rare or emerging resistant mechanisms include 1) the presence of plasmids that protect cells from the lethal effects of the ﬂuoroquinolones and 2) acquisition of a ﬂuoroquinolone modifying enzyme (Robicsek et al 2006; Robicsek et al 2006). Low level ﬂuoroquinolone resistant populations usually contain a single mutation in DNA gyrase or topoisomerase IV. The preferred or primary target varies with the bacteria species and the ﬂuoroquinolone. Key mutations usually occur in a unique region known as the quinolone resistant determin- ing region (QRDR) of either DNA gyrase or topoisomerase IV. Secondary mutations may also occur in genes outside of these regions, in genes encoding efﬂux pumps, membrane permeability and cell transport. High level resistant isolates contain multiple gene mutations both in primary and in secondary targets. In areas with preexisting low levels of ﬂuroquinolone resistance, exposure to suboptimal levels of Clinical Ophthalmology 2008:2(1) Moxiﬂoxacin hydrochloride ophthalmic solution O OH the new ﬂuoroquinolones will lead to rapid progression to double mutants and high level resistance (Hooper 2001b; Smith et al 2001; Zhanel et al 2002; Hwang 2004; Miller and Alfonso 2004). Figure 3 highlights the evolution of ﬂuoroquinolones resistance among ocular isolates recovered from postop- erative endophthalmitis cases from one region (Miller et al 2006). At base line (1990–1994), low level resistance to ciproﬂoxacin (10.3%) was evident, with no documented resistance to levoﬂoxacin, gatiﬂoxacin, or moxiﬂoxacin. Emergence of multistep mutants or subpopulations resistant to levoﬂoxacin and the 8 methoxy ﬂuoroquinolones were steeper and almost 3 times higher compared to ciproﬂoxa- cin during the initialﬁve years following ciproﬂoxacin’s introduction. Increasing resistance to ciproﬂoxacin and levoﬂoxacin doubled in the last 5 years. Resistant populations increased by 8.9% for gatiﬂoxacin and 5.1% for moxiﬂoxacin during that same time period. Spectrum of activity In vitro studies comparing minimal inhibitory concentra- tions (MICs) from the United States, Asia and Europe have documented the in vitro efﬁcacy of moxiﬂoxacin against a broad array of ocular and nonocular pathogens (Blondeau 1999; Krasemann, Meyer et al 2001; Zhanel, Ennis et al 2002; Caeiro and Iannini 2003; Dalhoff and Schmitz 2003; Hwang 2004; Keating and Scott 2004; Mah 2004). Emerging trends indicate enhanced activity and excellent coverage for S. pneumoniae, Haemophilus inﬂuenzae, and methicillin sus- ceptibile staphylococci compared to older ﬂuoroquinolones. There was near equivocal coverage for Enterobacteriaceae, Pseudomonas aeruginosa, and other nonfermenters, but 79