Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities

DOI: 10.1128/AAC.02498-16

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FIG 1
Survival-type antimicrobial susceptibility curves for Escherichia coli isolates (n = 158) and Klebsiella isolates (n = 87) from patients with urinary tract infections stratified on the basis of pHs of 6.0 (solid line) and 7.0 (dotted line).
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FIG 2
Fosfomycin MIC frequency in 158 Escherichia coli and 87 Klebsiella clinical isolates at pH 6.0 and 7.0 and probability of target attainment of an AUC/MIC of 23 against E. coli (right) and Klebsiella spp. (left) in serum (top) and urine (bottom) matrices for a fosfomycin dosing regimen consisting of a single dose of 3,000 mg in 10,000 virtual patients. PTA, probability of target attainment; AUC, area under the concentration-time curve.
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FIG 3
Molecular structure of fosfomycin and pK_a values derived from the Chemicalize database (https://chemicalize.com/#/calculation).
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FIG 4
Relationship between the microspecies distribution percentage for fosfomycin and pH adapted from the Chemicalize database (https://chemicalize.com/#/calculation).

TABLE 1

In vitro susceptibilities to fosfomycin of E. coli and Klebsiella spp. clinical isolates from patients with UTIs at pH 6.0 and 7.0^a

Microorganism	No. of strains	pH of test	No. of isolates with the following MIC (μg/ml):													MIC (mg/liter)			% of isolates
			No. of isolates with the following MIC (μg/ml):													MIC (mg/liter)			CLSI			EUCAST
			0.25	0.5	1	2	4	8	16	32	64	128	256	512	>512	50%	90%	Range	S	I	R	S	R
Escherichia coli	158	7.0	−	−	3	61	54	19	6	10	3	1	−	−	1	4	16	1 to >512	98	1	1	97	3
		6.0	−	9	63	52	12	13	5	2	1	−	−	−	1	2	8	0.5 to >512	99		1	98	2
Klebsiella spp.^b	87	7.0	−	−	−	−	−	−	2	2	−	23	21	22	17	256	>512	16 to >512	5	26	69	5	95
		6.0	−	−	−	−	−	2	3	6	15	26	19	7	9	128	512	8 to >512	30	30	40	13	87

↵a −, no isolate; S, susceptible; I, intermediate susceptibility; R, resistant; CLSI, Clinical and Laboratory Standards Institute interpretative criteria (susceptible, MIC of ≤64 μg/ml; intermediate, MIC of 128 μg/ml; resistant, MIC of ≥256 μg/ml; EUCAST, European Committee on Antimicrobial Susceptibility Testing interpretative criteria (susceptible, MIC of ≤32 μg/ml; resistant, MIC of ≥32 μg/ml).
↵b The species isolated included Klebsiella pneumoniae (n = 81) and K. oxytoca (n = 6).