Review of moxifloxacin hydrochloride ophthalmic solution in the treatment of bacterial eye infections

Figures & data

Figure 1 Basic 4-quinolone structure (adapted from Domagala 1994).

Figure 2 Moxifloxacin molecule

Table 1 Impact of core modification and potency to the fluoroquinolones

Substitution area	Structure/side effects relationship
R1	This area is part of the enzyme-DNA binding complex-inappropriate stereochemistry inhibits activity. A cyclopyl substitution here increases topoisomerase binding.
R2	Area closes to the gyrase binding site: bulky side chains lowers potency
R3–R4	These two groups interact with cleaved or damage DNA; no good substitutions/alternatives have been found
R-5	Substitutions here affects topoisomerase affinity, A NH2 or CH3 group adds gram-positive activity
R-6	Affects potency; NH2 or H possible, Interactions of (R6+7+8) are key
R-7	Interacts with DNA gyrase. Bulky side chain here impedes efflux; increases gram positive activity
R-8	Affects target affinity. A CH3 or OCH3 increases affinity against anaerobes

Adapted from Domagala (1994), Peterson (2001).

Figure 3 Evolution of fluoroquinolone resistance among coagulase negative staphylococci recovered from patients with post operative endophthalmitis (N = 78 isolates) (derived from Miller and Flynn 2006).

Table 2 Comparative in vitro susceptibility of ciprofloxacin, gatifloxacin, and moxifloxacin against select nonocular pathogens

Country	Time period	Pathogen	N	MIC 90 μg/mL			Reference
				Moxifloxacin	Gatifloxacin	Ciprofloxacin
Canada	Collected prior to 1999
		S. aureus
		MSSA	365	0.125 (S)a	0.25 (S)	NDb	Blondeau et al 2000
		MRSA	42	2 (R)	4 (R)	ND
		S. pneumoniae	399	0.25 (S)	0.25–0.5 (S)	ND
		H. influenzae	199	0.063 (S)	0.016 (S)	0.031 (S)
		P. aeruginosa	1472	16	8 (R)	4 (R)
		M. catarrhalis	337	0.063 (S)	0.031 (S)	0.031 (S)
		P. mirabilis	30	0.5	0.25 (S)	0.031 (S)
USA	1999–2001	S. pneumoniae	3304	0.25 (S)	0.5 (S)	2	Jones et al 2003
		H. influenzae	3371	0.03 (S)	0.03 (S)	0.03 (S)
		M. catarrhalis	1656	0.06 (S)	0.03 (S)	0.03 (S)
USA	April–December 1996	MSSA	34	0.06 (S)		1 (S)	Fass 1997
		MRSA	20	4 (R)		>32 (R)
		MSSE	23	0.12 (S)		0.5 (S)
		MRSE	29	2 (R)		>32 (R)
		S. pneumoniae	50	0.25 (S)		1
		H. influenzae	45	0.03 (S)		0.015 (S)
		P. mirabilis	33	2		0.25 (S)
		P. aeruginosa	26	= 32		≥32 (R)
Taiwan	1998–1999	MSSA	58	0.06 (S)		0.5 (S)	Sheng Wang-Huei, et al 2001
		MRSA	60	2 (R)		16 (R)
		MSSE	58	0.12 (S)		1 (S)
		MRSE	60	8 (R)		128 (R)
		S. pneumoniae	42	4 (R)		128
		P. aeruginosa	60	2		0.25 (S)
Europe (14), Israel (1), South America (3)	April 1997–February 1999	MSSA	434	0.06 (S)	0.12 (S)	0.5 (S)	Milatovic et al 2000
		MRSA	457	4 (R)	4 (R)	>16 (R)
		MSSE	214	1 (I)	2 (R)	16 (R)
		MRSE	436	2 (R)	2 (R)	>16 (R)
		CoNS, other	111	8 (R)	8 (R)	>16 (R)
		S. pneumoniae	427	.25 (S)	.5 (S)	2
		S. viridans group	97	0.25	0.5 (S)	4
		H. influenzae	224	0.03 (S)	.015 (S)	0.15 (S)
		P. aeruginosa	615	>16	>16	>16 (R)
		P. mirabilis	319	16	4(R)	4 (R)
		S. marcescens	211	4	2 (S)	2 (I)

a Interpretations were in accordance with the Clinical and Laboratory Standard Institute (CLSI) Performance for Antimicrobial Susceptibility Testing; Seventeenth Informational Informational Supplement. M100-S17. S, sensitive, I, intermediate, R, resistant.

b ND = not done. No CLSI standards for S. pneumoniae or S. viridans group and ciprofloxacin. No CLSI standards for gatifloxacin and moxifloxacin and P. aeruginosa. No CLSI standards for moxifloxacin S. marcescens, S. viridans group, and P. mirabilis.

Abbreviations: MIC₉₀, concentration that inhibits 90% of isolates tested; MSSA, methicillin sensitive Staphylococcus aureus; MRSA, methicillin resistant Staphylococcus aureus; MSSE, methicillin sensitive Staphylococcus epidermidis; MRSE, methicillin resistant Staphylococcus epidermidis; P. aeruginosa, Pseudomonas aeruginosa, M. catarrhalis, Moraxella catarrhalis; S. pneumoniae, Streptococcus pneumoniae; H. influenzae; Haemophilus influenzae; P. mirabilis, Proteus mirabilis; S. aureus, Staphylococcus aureus; S. viridans group; Streptococcus viridans group; CoNS other, coagulase negative staphylococci other than S. epidermidis; S. marcescens, Serratia marcescens.

Table 3 Comparative MIC₉₀s for moxifloxacin, gatifloxacin, and ciprofloxacin against select ocular pathogens

	Type	Ocular source	Number	MIC 90 μg/mL			Time Period	Reference
				Moxifloxacin	Gatifloxacin	Ciprofloxacin
S. aureus		Cornea
	FQS		25	0.047 (S)a	0.22 (S)	0.5 (S)	1993–2003	Kowalski et al 2003
	FQR		25	4 (R)	12 (R)	128 (R)
	FQS	Conjunctiva isolates	20	0.094 (S)	0.125 (S)	0.5 (S)	1998–2002	Kowalski et al 2005
	FQR		20	6.0 (R)	64 (R)	>32 (R)
	NOS	All ocular	21	0.25 (S)	0.125 (S)	0.25 (S)	2002–2004	Oliveira et al 2007
	MSSA	All ocular	53	1.5 (R)	1.5 (R)	32 (R)	2001–2006	Miller 2006, unpublished
	MRSA		39	32 (R)	32 (R)	32 (R)
Coagulase negative		cornea
Staphylococci	FQS
			10	0.125 (S)	0.19 (S)	0.3/8 (S)	1993–2002	Kowalski et al 2003
	FQR		10	3 (R)	3 (R)	64 (R)
	FQS	Intraocular fluids	10	0.05 (S)	0.09 (S)	0.13 (S)	1993–2000	Mather et al 2002
	FQR		10	2.5 (R)	2 (R)	2.0 (R)
Coagulase Negative	NOS	all ocular	66	>32 (R)	>32 (R)	>32 (R)	2001–2006	Miller 2006, unpublished
Staphylococci, Coagulase		All ocular					2002–2004	Oliveira et al 2007
NegativeStaphylococci,
	FQS		57	0.75 (I)	1 (I)	2 (I)
	FQR		21	3 (R)	2 (R)	>32 (R)
S. pneumoniae		Cornea	20	0.19 (S)	0.25 (S)	2 (I)	1993–2002	Kowalski 2003
		Conjunctiva	20	0.09 (S)	0.19 (S)	0.75 (S)	1998–2002	Kowalski 2005
		Intraocular fluids	10	0.09 (S)	0.22 (S)	0.75 (S)	1993–2000	Mather et al 2002
		All ocular	20	0.19 (S)	0.19 (S)	3 (R)	2001–2006	Miller 2006, unpublished
		All ocular	16	0.12 (S)	0.19 (S)	1 (S)	2002–2004	Oliveira et al 2007
P. aeruginosa	FQS	Cornea	25	0.75	0.38	0.094 (S)	1993–2002	Kowalski et al 2003
		All ocular	40	>32	>32	>32 (R)	2001–2006	Miller 2006, unpublished
		All ocular	23	2	1	0.25 (S)	2002–2004	Olivera et al 2007
H. influenzae		Cornea	10	0.19 (S0)	0.06 (S)	0.03 (S)	1993–2002	Kowalski et al 2003
		Conjunctiva	20	0.12 (S)	0.25 (S)	1.0 (S)	1998–2002	Kowlaski et al 2005
		All ocular	21	0.5 (S)	0.32 (S)	0.19 (S)	2002–2004	Oliveira et al 2007

a Interpretations were in accordance with the Clinical and Laboratory Standard Institute (CLSI) Performance for Antimicrobial Susceptibility Testing; Seventeenth Informational Informational Supplement. M100-S17. S, sensitive; I, intermediate; R, resistant.

b No CLSI standards for S. pneumoniae and ciprofloxacin. No CLSI standards for gatifloxacin and moxifloxacin and P. aeruginosa.

Abbreviations: MSSA, methicillin sensitive Staphylococcus aureus; MRSA, methicillin resistant Staphylococcus aureus; MIC₉₀, concentration that inhibits 90% of isolates tested; FQS, fluoroquinolone sensitive; FQR, fluroquinolone resistant; NOS, Staphylococcus aureus, not otherwise specified or Coagulase negative staphylococci not otherwise specified.

Table 4 Regional and geographic variation in endemic fluoroquinolone resistance (%) among ocular pathogens

Region	Fluoroquinolone					Reference
	Ciprofloxacin	Gatifloxacin	Moxifloxacin	Number of Isolates	Time Period
Europe	12.4	5.5	ND	532	July 2001–Dec 2002	Morrissey et al 2004
France	12.4	5.6	ND
Germany	4.6	1.5	ND
Italy	19.9	4.6	ND
Spain	15.9	9.8	ND
Sweden	2.0	0	ND
UK	8.3	8.3	ND
USA (Northeast)	28.3	13.7	20	350	1993–2005	Mather et al 2002; Kowlaski et al 2003; Kowalski et al 2005
USA (South Florida)	30.1	16.7	23.3	431	2000–2006	Miller 2006 (unpublished)
Brazil	14.2	11.9	11.9	183	2002–2004	Oliveira et al 2007

ND=Not done.

Table 5 Penetration studies of moxifloxacin and comparators into aqueous and vitreous humor

Route of Administration	Dosing	Dosage	Moxifloxacin		Gatifloxacin		Ciprofloxacin		Reference
			Aqueous (μg/mL)	Vitreous (μg/mL)	Aqueous (μg/mL)	Vitreous (μg/mL)	Aqueous (μg/mL)	Vitreous (μg/mL)
Topical	1 drop/2 hours × 3 days	43 drops	2.28 ± 1.23	0.11 ± 0.05	ND	ND	ND	ND	Hariprasad et al 2005
	1 drop/6 hours × 3 days	22	0.88 ± 0.88	0.06 ± 0.06	ND	ND	ND	ND	Hariprasad et al 2005
	1 drop/10 min prior to surgery	4 drops	1.80 ± 1.25		0.48 ± 0.34				Kim et al 2005
	4×/day × 3 days plus 3 drops 1 hour prior to surgery	15 drops	1.31 ± 0.46		0.63 ± 0.30		0.15 ± 0.11		Solomon et al 2005
	4 times/day 1 day prior and 1 drop prior to surgery	5 drops	1.86 ± 0.23		0.94 ± 0.15				McCulley et al 2006
	4 drops pre surgery	4 drops	1.55 ± 0.86		0.74 ± 0.66				Katz et al 2005
	4 times a day/1 day before and 4 drops, pre surgery	4 drops	1.61 ± 0.71		0.91 ± 0.54
	4 × 2 days pre op	8 drops	0.38 ± 0.32		0.19 ± 0.23				Ong-Tone et al 2007
	4 × 2 days pre op plus 3 drops 2 hours prior to surgery	11 drops	2.16 ± 1.12		0.82 ± 0.31
	4 × 3 days before surgery	12 drops		0.011 ± 0.008		0.008 ± 0.006			Costello et al 2006
Oral	2 tablets (400 mg) at 14 and 3 hours before surgery	800 mg		1.55 ± 0.33					Fuller et al 2006
	2 tablets, evening prior to surgery and 3 hours before surgery	800 mg	1.34 ± 0.66	1.58 ± 0.80					Hariprasad et al 2006
	Single tablet 1–2 hours before surgery	400 mg	0.21 ± 0.21	0.09 ± 0.09					Vedantham et al 2005
	Single tablet, 10 hours before surgery	400 mg	2.33 ± 0.85						Garcia- Saenz et al 2001
	Single dose Prior to surgery	400 mg	1.17 ± 0.40 (10 hours)						Walter et al 2007
	2 tablets, 12 hours apart	400 mg	1.23 ± 0.55 (12 hours)						Kampougeris et al 2007

Figure 4 Factors affecting favorable outcomes during antimicrobial therapy.

Table 6 Comparative MIC₅₀s, MIC₉₀s, and calculated pharmacodynamic indices for moxifloxacin and gatifloxacin for coagulase-negative staphylococci versus reported aqueous concentrations

Drug	Source	Cmax	Calculated MIC/MPC target value	MIC50	MIC50	MIC90
				(Mather et al 2002)	(Miller et al 2006)
Moxifloxacin	Aqueous	0.38 ± 0.32	≤0.038	0.05 (FQS) 2.5 (FQR)	0.09	4
		0.88 ± 0.88	≤0.088
		1.31 ± 0.46	≤0.131
		1.55 ± 0.86	≤0.155
		1.61 ± 0.71	≤0.161
		1.80 ±1.25	≤0.180
		1.86 ± 0.23	≤0.186
		2.16 ± 1.12	≤0.216
		2.28 ± 1.23	≤0.228
Gatifloxacin	Aqueous	0.19 ± 0.23	≤0.019	0.09 (FQS) 2.0 (FQR)	0.19	4
		0.48 ± 0.34	≤0.048
		0.63 ± 0.30	≤0.063
		0.74 ± 0.66	≤0.074
		0.82 ± 0.31	≤0.082
		0.91 ± 0.54	≤0.091
		0.94 ± 0.15	≤0.094

Derived from Mather et al (2002), Miller and Flynn (2006).

Abbreviations: MIC₉₀, concentration that inhibits 90% of isolates tested; MIC₅₀, concentration that inhibits 50% of isolates tested; FQS, fluoroquinolone sensitive; FQR, fluroquinolone resistant.

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