Daptomycin-Oxacillin Combinations in Treatment of Experimental Endocarditis Caused by Daptomycin-Nonsusceptible Strains of Methicillin-Resistant Staphylococcus aureus with Evolving Oxacillin Susceptibility (the “Seesaw Effect”)

DOI: 10.1128/AAC.00487-10

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FIG. 1.
Population analyses of study strains upon exposure to a range of DAP (left panel) or OX (right panel) concentrations. These data represent the means (± SD) for two separate assays. conc., concentration.
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FIG. 2.
OX time-kill analyses. Six DAP^s and DAP^r strain pairs were used for these experiments. (A) CB1118-CB2205; (B) MRSA 11/11-REF2145; (C) CB1482-CB184; (D) BMC1001-BMC1002; (E) CB5053-CB5054; (F) CB5035-CB5036. Time-kill experiments were performed using Mueller-Hinton broth with a 10⁶-CFU/ml inoculum in the presence of 0 to 256 μg/ml OX.
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FIG. 3.
In vitro synergy kill curves for DAP^r REF2145 (A) and CB5054 (B) strains. These two strain sets were used in the experimental IE studies detailed in the text. The growth curve for the no-antibiotic growth control for these experiments is not shown but was identical to the growth curve for both strains with one-quarter of the MIC of DAP.

TABLE 1.

Strains used in this study

Strain (pulsotype)^a	SCCmec type	Description	MIC (μg/ml)		Reference(s)
Strain (pulsotype)^a	SCCmec type	Description	DAP	OX	Reference(s)
CB1118 (USA400)	IV	Selected in vitro by serial passage in DAP	0.5	24	15, 29
CB2205 (USA400)	IV	Selected in vitro by serial passage in DAP	8	6
MRSA 11/11 (USA300)*	IV	Clinical endocarditis isolate	0.38	32	31
REF2145 (USA300)*	IV	Clinical endocarditis isolate	4	6
CB1482 (USA500)	IV	Clinical bloodstream isolate	0.5	64	15
CB184 (USA500)	IV	Clinical bloodstream isolate	2	16
BMC1001 (USA500)	IV	Clinical bloodstream isolate	0.5	>256	This study
BMC1002 (USA500)	IV	Clinical bloodstream isolate	2	128
CB5053 (USA100)*	II	Clinical bloodstream isolate	0.5	64	This study
CB5054 (USA100)*	II	Clinical bloodstream isolate	2	24
CB5035 (USA100)	II	Clinical bloodstream isolate	0.38	192	This study
CB5036 (USA100)	II	Clinical bloodstream isolate	2	96

TABLE 2.

MRSA 11/11-REF2145 and CB5053-CB5054 counts in target tissues with DAP and/or OX treatment in the IE model

Group (no. of animals)^a	S. aureus density (log₁₀ CFU/g tissue) in^b:
Group (no. of animals)^a	Vegetation	Kidney	Spleen
Control without treatment
MRSA 11/11 (8)	7.74 ± 0.79	5.51 ± 0.63	5.28 ± 0.56
MRSA REF2145 (8)	8.84 ± 0.56	6.29 ± 0.67	6.15 ± 0.65
CB5053 (6)	7.74 ± 0.80	5.98 ± 0.98	5.84 ± 0.53
CB5054 (6)	8.76 ± 0.18	6.63 ± 0.75	5.95 ± 0.65
Treatment
MRSA 11/11 (12 mg/kg DAP i.v. once daily) (7)	1.58 ± 0.59	0.53 ± 0.28	0.60 ± 0.16
MRSA REF2145 (12 mg/kg DAP i.v. once daily) (7)	7.93 ± 1.12*	6.74 ± 0.71*	5.52 ± 1.23*
MRSA 11/11 (200 mg/kg OX i.m. t.i.d.) (8)	5.96 ± 2.23	3.99 ± 1.43	4.07 ± 1.17
MRSA REF2145 (200 mg/kg OX i.m. t.i.d.) (8)	7.21 ± 1.39	5.09 ± 1.99	4.79 ± 1.51
MRSA REF2145 (DAP-OX) (8)	4.20 ± 1.61**	2.90 ± 1.50**	3.12 ± 0.81**
CB5053 (12 mg/kg DAP i.v. once daily) (6)	1.71 ± 0.96	0.95 ± 0.60	1.07 ± 0.92
CB5054 (12 mg/kg DAP i.v. once daily) (6)	8.34 ± 0.83*	6.32 ± 1.31*	5.78 ± 1.29*
CB5053 (200 mg/kg OX i.m. t.i.d.) (7)	6.18 ± 1.74	4.01 ± 1.82	3.88 ± 1.19
CB5054 (200 mg/kg OX i.m. t.i.d.) (6)	8.96 ± 0.44	6.35 ± 1.02	5.68 ± 0.80
CB5054 (DAP-OX) (10)	5.70 ± 1.98**	3.88 ± 1.25**	3.99 ± 0.95**

↵a 12 mg/kg DAP intravenously (i.v.) once daily is equivalent to a dose of 6 mg/kg once daily in humans (7).
↵b *, P value of <0.001 relative to the value for DAP^s MRSA 11/11 or CB5053 with DAP treatment; **, P value of <0.05 relative to the value for REF2145 or CB5054 with OX-only or DAP-only treatment.