Activity of LBM415 Compared to Those of 11 Other Agents against Haemophilus Species

Tatiana Bogdanovich; Kathy A. Smith; Catherine Clark; Glenn A. Pankuch; Gengrong Lin; Pamela McGhee; Bonifacio Dewasse; Peter C. Appelbaum

doi:10.1128/AAC.00106-06

DOI: 10.1128/AAC.00106-06

Article Figures & Data

Tables

TABLE 1.

MICs (μg/ml) of compounds against 254 H. influenzae and 23 H. parainfluenzae strains

Antibiotic	MIC for H. influenzae strains								MIC for H. parainfluenzae (n = 23)
	β-Lactamase positive (n = 102)		β-Lactamase negative (n = 130)		BLNAR (n = 22)		All strains (n = 254)		MIC for H. parainfluenzae (n = 23)
	Range	MIC₅₀/MIC₉₀	Range	MIC₅₀/MIC₉₀	Range	MIC₅₀/MIC₉₀	Range	MIC₅₀/MIC₉₀	Range	MIC₅₀/MIC₉₀
LBM415	0.06-16	2/8	0.03->16	2/4	0.12->16	1/8	0.03->16	2/8	0.25-8	2/4
Erythromycin	0.5->64	4/8	0.06->64	4/16	2-16	4/16	0.06->64	4/16	1-8	4/8
Azithromycin	0.12->64	1/2	≤0.03->64	1/2	0.25-4	1/2	≤0.03->64	1/2	0.06-2	0.5/1
Clarithromycin	1->64	8/16	≤0.03->64	8/16	2-32	4/16	≤0.03->64	8/16	0.5-16	4/16
Amoxicillin	8->32	>32/>32	0.12-8	0.5/2	1->32	8/16	0.12->32	4/>32	0.06->32	0.5/>32
Amoxicillin- clavulanate	0.12-8	1/4	0.12-8	0.5/2	1->32	8/16	0.12->32	0.5/4	0.06->32	0.5/4
Cefpodoxime	0.015-4	0.06/0.25	0.03-2	0.06/0.25	0.25->16	2/4	0.015->16	0.06-0.5	≤0.008->16	0.03/0.5
Cefuroxime	0.25-32	1/2	0.12-16	1/2	1->64	4/64	0.12->64	1/4	0.12->64	0.25/2
Cefdinir	0.12-2	0.25/1	0.06-4	0.25/1	0.5->16	2/16	0.06->16	0.5/1	0.06->16	0.12/1
Ciprofloxacin	0.008->2	0.008/0.015	0.004->2	0.008/0.015	0.004->2	0.008/0.015	0.004->2	0.008/0.015	0.004-0.03	0.008/0.015
Levofloxacin	0.008-2	0.015/0.015	0.004-4	0.015/0.03	0.008-2	0.015/0.25	0.004-4	0.015/0.03	0.004-0.06	0.015/0.03
Gatifloxacin	0.004-8	0.008/0.015	0.002-2	0.008/0.015	0.004-1	0.008/0.015	0.002-8	0.002/0.008	0.004-0.12	0.015/0.03
Moxifloxacin	0.008->2	0.015/0.03	0.008->2	0.015/0.06	0.008->2	0.015/0.06	0.008->2	0.015/0.06	0.015-0.25	0.06/0.12
Gemifloxacin	≤0.001-2	0.002/0.008	≤0.001-2	0.002/0.008	≤0.001-0.5	0.002/0.008	≤0.001-2	0.002/0.008	0.004-0.06	0.008/0.03
Trimethoprim- sulfamethoxazole	≤0.03->16	0.5/16	0.12->16	0.5/16	≤0.03->16	0.5/16	≤0.03->16	0.5/16	0.06->16	0.5/16
Tetracycline	0.12-32	0.25/0.5	≤0.06-1	0.25/0.5	0.12-0.5	0.25/0.5	≤0.06-32	0.25/0.5	0.25-16	0.5/1

TABLE 2.

Time-kill analyses of 10 Haemophilus strains^a

Drug and dose (multiplicity of MIC)	No. of strains killed at indicated time (h)^b
	3			6			12			24
	−1	−2	−3	−1	−2	−3	−1	−2	−3	−1	−2	−3
LBM415 (MICs, 0.125-4 μg/ml)
4	2	1	0	7	3	1	10	8	6	10	10	9
2	1	1	0	5	3	0	9	5	5	10	10	8
1	1	0	0	4	0	0	6	4	3	10	8	5
Erythromycin (MICs, 0.5-8 μg/ml)
4	7	3	0	9	6	3	10	10	8	10	10	10
2	6	0	0	8	5	2	10	9	5	10	10	9
1	3	0	0	6	2	0	9	6	4	10	8	7
Azithromycin (MICs, 0.125-2 μg/ml)
4	7	4	1	9	7	3	10	10	10	10	10	10
2	7	3	1	7	6	3	10	9	8	10	10	9
1	4	1	0	5	3	2	8	7	3	10	9	6
Clarithromycin (MICs, 0.25-8 μg/ml)	7	2	0	8	6	2	10	10	6	10	10	10
4	3	2	0	6	4	1	9	8	4	10	10	10
2	2	0	0	5	3	1	7	4	3	9	6	4
1
Amoxicillin-clavulanate (MICs, 0.25-8 μg/ml)
4	4	0	0	7	1	0	10	9	2	10	10	10
2	2	0	0	7	1	0	10	8	2	10	10	10
1	2	0	0	5	1	0	9	6	2	10	9	8
Cefpodoxime (MICs, 0.06-2 μg/ml)
4	3	0	0	9	2	0	10	10	2	10	10	10
2	1	0	0	6	2	0	10	8	2	10	10	10
1	0	0	0	6	1	0	9	6	1	10	9	6
Cefuroxime (MICs, 0.5-16 μg/ml)
4	3	0	0	9	1	0	10	9	4	10	10	10
2	2	0	0	8	1	0	10	8	3	10	10	10
1	2	0	0	5	1	0	9	6	2	10	9	8
Cefdinir (MICs, 0.25-4 μg/ml)
4	1	0	0	10	2	0	10	9	2	10	9	9
2	2	0	0	8	1	0	10	8	2	10	9	8
1	1	0	0	6	1	0	10	5	0	9	7	4
Ciprofloxacin (MICs, 0.008-0.015 μg/ml)
4	9	4	0	10	6	2	10	10	7	10	10	10
2	8	2	0	10	4	1	10	10	6	10	10	10
1	3	1	0	9	1	1	1	8	3	10	10	10
Levofloxacin (MICs, 0.008-0.03 μg/ml)
4	10	5	1	10	8	2	10	10	9	10	10	10
2	9	3	0	10	7	1	10	10	8	10	10	10
1	8	0	0	9	4	0	9	9	4	9	9	9
Gatifloxacin (MICs, 0.004-0.03 μg/ml)
4	10	7	0	10	10	4	10	10	9	10	10	10
2	9	3	0	10	6	2	10	10	7	10	10	10
1	4	1	0	8	2	1	10	9	2	9	9	8
Moxifloxacin (MICs, 0.008-0.06 μg/ml)
4	10	5	3	10	9	6	10	9	9	10	10	10
2	9	4	1	10	8	2	10	8	8	10	10	10
1	4	2	0	6	3	1	10	7	3	10	10	9

↵ a Nine H. influenzae and one H. parainfluenzae strain.
↵ b −1, 90% killing; −2, 99% killing; −3, 99.9% killing.

TABLE 3.

MICs and PAEs of six H. influenzae strains

Drug	MIC range (μg/ml)	Mean PAE (range) (h)^a
LBM415	0.5-4.0	1.2 (0.8-2.2)
Erythromycin	2.0-8.0	3.1 (2.0-4.4)
Azithromycin	0.5-2.0	7.1 (5.6-9.2)
Clarithromycin	2.0-8.0	3.4 (2.4-4.6)
Amoxicillin-clavulanate	0.25-1.0	0.3 (0.0-0.9)
Cefpodoxime	0.06-0.25	0.2 (0.1-0.6)
Cefuroxime	0.5-2.0	0.6 (0.1-1.4)
Cefdinir	0.25-0.5	0.6 (0.2-1.8)
Ciprofloxacin	0.004-0.015	2.2 (1.6-3.4)
Levofloxacin	0.008-0.015	3.8 (2.8-5.0)
Gatifloxacin	0.004-0.015	3.4 (1.9-6.2)
Moxifloxacin	0.008-0.03	3.6 (2.4-5.4)

↵ a PAE induced by 1 h of exposure at 10× the MIC.

TABLE 4.

Results of multistep resistance selection by LBM415 and comparators^a

Strain	Drug^b	MIC (μg/ml)		Day of resistance	Cross-resistance MIC (μg/ml)
		Initial	Resistance
		Initial	Resistance		LBM	AZM	ERY	CLR	AMX	CPD	MOX
110-019	LBM	1	8	17	4	2	32	16	1	0.25	0.125
	AZM	1	8	15	1	8	>32	16	2	0.25	0.06
	ERY	4	32	14	4	2	16	32	2	0.25	0.125
	CLR	4	32	21	4	2	64	32	2	0.25	0.125
	MOX	0.06	0.5	39	1	1	16	8	2	0.25	0.25
112-048	LBM	4	16	50
	AZM	1	8	34	16	8	>32	32	1	0.25	0.03
	ERY	4	64	21	16	2	32	32	2	0.25	0.03
	CLR	4	32	24	4	2	64	16	1	0.06	0.03
	MOX	0.016	0.125	32	16	2	>64	16	1	0.125	0.125
621-049	LBM	2	16	20	8	2	>32	16	0.5	0.125	0.125
	AZM	2	16	47	4	16	>64	64	0.5	0.125	0.125
	ERY	8	>64	31	4	4	>64	32	0.5	0.25	0.06
	CLR	8	16	50
	MOX	0.06	0.5	26	4	2	32	8	0.5	0.125	0.5
HI 30	LBM	0.5	4	15	2	0.25	32	2	1	0.125	0.06
	AZM	0.25	4	20	2	4	32	8	2	0.25	0.06
	ERY	1	32	14	0.25	0.5	32	8	4	0.25	0.03
	CLR	1	8	14	1	0.5	16	8	4	0.5	0.03
	MOXI	0.03	0.25	35	4	1	16	8	4	0.25	0.25
153-008	LBM	1	8	14	8	2	32	8	0.5	0.06	0.03
	AZM	1	>64	34	2	32	>32	>64	0.5	0.125	0.03
	ERY	4	64	21	2	2	32	8	0.5	0.06	0.03
	CLR	4	32	46	2	2	32	16	0.5	0.125	0.03
	MOX	0.03	0.06	50
110-061	LBM	1	8	15	8	2	>32	16	1	0.25	0.06
	AZM	1	16	22	2	16	>32	>64	1	0.25	0.06
	ERY	8	64	25	4	2	64	64	2	0.25	0.06
	CLR	8	64	40	8	2	64	64	1	0.5	0.06
	MOX	0.03	0.25	34	2	1	16	8	1	0.25	0.5
204-001	LBM	8	8	50
	AZM	1	1	50
	ERY	4	32	31	16	1	16	8	0.25	0.04	0.25
	CLR	4	8	50
	MOX	0.125	0.25	50
113-012	LBM	16	32	50
	AZM	2	4	50
	ERY	16	>64	31	16	4	>64	32	2	0.25	0.03
	CLR	16	32	50
	MOX	0.03	0.06	50
153-026	LBM	4	64	15	16	2	32	8	0.5	0.06	0.03
	AZM	2	32	24	2	64	>32	>64	0.5	0.125	0.03
	ERY	8	64	14	8	2	32	32	0.5	0.125	0.03
	CLR	8	64	48	4	4	64	32	0.25	0.06	0.03
	MOX	0.03	0.06	50
204-018	LBM	4	32	20	32	2	>32	16	0.5	0.125	0.03
	AZM	2	64	17	4	64	>64	>32	0.5	0.125	0.03
	ERY	16	>64	31	8	4	64	64	0.5	0.125	0.03
	CLR	8	64	31	4	4	>64	64	1	0.25	0.03
	MOX	0.03	0.06	50

↵ a Amoxicillin-clavulanate and cefpodoxime yielded no resistant clones in any of the strains tested at the maximum of 50 passages. Their cross-resistance patterns to clones selected by other agents are provided for completeness.
↵ b LBM, LBM415; AZM, azithromycin; ERY, erythromycin; CLR, clarithromycin; MOX, moxifloxacin.