In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant Klebsiella pneumoniae

Figures & data

Figure 1 The sketch of PD parameters.

Abbreviations: –1KT, –1Log kill time; –2KT, –2Log kill time; –3KT, –3Log kill time; SRT, regrowth recovery time; +1RT, +1Log growth time; AAKC, area above kill curve; AST, analysis start time; MKD, maximum kill down; MKT, maximum kill time; PD, pharmacodynamics; RT, bacterial growth recovery time; TAAKC, total area above kill curve; T–1KT, total –1Log kill time.

Table 1 Characteristics of three KPC-producing Klebsiella pneumoniae strains

Characteristics	2887	3155	18253
Specimen	Urine	Sputum	Blood
MLST	ST420	ST14	ST11
Resistance genes	blaSHV-11 blaSHV-75	blaSHV-28	blaSHV-II blaSHV-12 blaKPC-2
MIC (mg/L) ATM	0.5	0.5	>128
CZ	4	4	>128
CXM	8	8	>128
FOX	4	2	>128
FEP	0.125	0.l25	128
CAZ	0.25	0.5	>128
CRO	0.25	0.03	>128
TZP	2/4	32/4	> 128/4
AMC	8/4	2/1	> 128/64
CSL (1:1)	l/0.5	l/0.5	> 128/64
IMP	0.25	0.25	16
MEM	0.06	0.06	>32
ETP	0.25	0.25	256
LVX	0.5	0.06	128
CIP	0.25	0.25	>128
GM	1	1	2
AMK	2	2	4
TGC	1	1	2
SXT	>8/152	2/38	>8/152
COL	>32	>32	>32
FM	4	8	16

Abbreviations: AMC, amoxicillin–clavulanic acid; AMK, amikacin; ATM, aztreonam; CAZ, ceftazidime; CIP, ciprofloxacin; COL, colistin; CRO, ceftriaxone; CSL, cefoperazone-sulbactam; CXM, cefuroxime; CZ, cefazolin; ETP, ertapenem; FEP, cefepime; FM, fosfomycin; FOX, cefoxitin; GM, gentamicin; IMP, imipenem; LVX, levofloxacin; MEM, meropenem; MIC, minimum inhibitory concentration; MLST, multilocus sequence typing; SXT, trimethoprim–sulfamethoxazole; TGC, tigecycline; TZP, piperacillin–tazobactam.

Figure 2 In vitro dynamic model time–kill assays using concentrations of FM, AMK, and COL (either alone or in combination) against three CR-Kp strains.

Notes: (A) and (B) monotherapy or combination therapy, respectively, against isolate 2887; (C) and (D) monotherapy or combination therapy, respectively, against isolate 3155; (E) and (F) monotherapy and combination therapy, respectively, against isolate 18253. The dotted lines indicate monotherapy, and the solid lines indicate combination therapy. Antibiotic concentrations are denoted by different symbols.
Abbreviations: AMK, amikacin; COL, colistin; CR-Kp, colistin-resistant Klebsiella pneumoniae; FM, fosfomycin; q8h, every 8 hours; q12h, every 12 hours; qd, once daily.

Table 2 PD parameters of different regimens against the three KPC-producing Klebsiella pneumonia

Isolates	Dosage regimen	MKD (ΔLogCFU/mL)	MKT (h)	AAKC (ΔLogCFU/mL)	RT (h)	-1KT (h)	-2KT (h)	-3KT (h)	SRT (h)	+ 1 RT (h)	T-1KT (h)	T-2KT (h)	T-3KT (h)	1E (LogCFU/mL h^1)
2887	FM (8 g q8h)	-3.0	3.9	23.5	13.2	9.9	5.9	1.0	9.1	15.4	9.9	5.9	1.0	80
	AMK (15 mg/kg qd)	-6.3	1.4	103.3	>24	23.8	17.6	16.2	22.6	NA	23.9	17.6	16.2	185.8
	COL (75,000 lU/kg q 1 2h)	-1.3	3.8	5.5	7.5	2.4	NA	NA	3.7	8.5	2.4	NA	NA	39.6
	FM (8 g q8h)/AMK (15 mg/kg qd)	-6.3	1.4	138.7	>24	23.6	23.7	23.6	22.6	NA	23.9	23.7	23.6	219.9
	FM (8 g q8h)/COL (75,000 lU/kg q 12h)	-4.4	3.7	29.6	13.8	9.8	8.2	4.1	9.9	NA	8.2	4.1	9.9	108
3155	FM (8 g q8h)	-3.4	3.7	28.2	13.9	1 1.8	8.1	2.5	10.2	15.2	1 1.8	8.1	2.5	80.4
	AMK (15 mg/kg qd)	-6.5	1.4	105.5	23.5	22.1	20.5	18.5	22.2	22.1	20.5	18.5	22.1	190.7
	COL (75,000 lU/kg q 1 2h)	-6.2	1.4	41.8	9.4	8.9	9.5	7.9	8.0	9.8	8.9	9.5	7.9	77
	FM (8 g q8h)/AMK (15 mg/kg qd)	-6.3	2.8	1 18.2	>24	23.6	22.7	19.9	21.2	NA	23.6	22.7	20.7	201.1
	FM (8 g q8h)/COL (75,000 lU/kg q 12h)	-5.9	4.4	124.5	>24	23.8	23.7	23.5	19.6	NA	23.9	23.7	23.5	204.7
18253	FM (8 g q8h)	-0.6	0.9	0.8	1.9	NA	NA	NA	1.0	4.7	NA	NA	NA	25.2
	AMK (15 mg/kg qd)	-6.9	1.2	64.4	16.1	14.3	13.3	12.4	14.8	19.7	14.3	13.3	12.4	137.24
	COL (75,000 lU/kg q 1 2h)	-0.4	1.0	0.4	1.9	NA	NA	NA	0.9	3.0	NA	NA	NA	19.6
	FM (8 g q8h)/AMK (15 mg/kg qd)	-6.2	4.9	86.1	>24	21.5	17.6	13.5	19.12	NA	21.5	17.6	13.5	173.72
	FM (8 g q8h)/COL (75,000 lU/kg q 12h)	-1.9	3.9	26.9	>24	13.3	NA	NA	20.1	NA	13.3	NA	NA	111.6

Abbreviations: –1KT, –1Log kill time; –2KT, –2Log kill time; –3KT, –3Log kill time; +1RT, +1Log growth time; AAKC, area above kill curve; AMK, amikacin; COL, colistin; FM, fosfomycin; MKD, maximum kill down; MKT, maximum kill time; IE, the area between the control growth. and antibacterial killing curves; NA, Not Applicable; PD, pharmacodynamics; q8h, every 8 hours; q12h, every 12 hours; qd, once daily; RT, bacterial growth recovery time; SRT, regrowth recovery time; T–1KT, Total –1Log Kill Time; T–2KT, Total –2Log Kill Time; T–3KT, Total –3Log Kill Time.

Figure S1 (A–F) The time–concentration curves of antibiotics in the Pharmacokinetics Auto Simulation System 400.

Abbreviations: FM, fosfomycin; AMK, amikacin, COL, colistin; q8h, every 8 hours; q12h, every 12 hours; qd, once daily.

Figure S2 Pharmacokinetics Auto Simulation System 400.

Table S1 PK parameters of different regimens

Regimens (11-13)	t1/2ß(h)	AUC (mgh/L)	CL (mL/min)	V (L)	Cmax (mg/L)
AMK 15 mg/kg once daily	2.4±0.5	154.5±29.9	112.8±9.2	11.2± 1.8	76
COL 2.5 mg/kg every 12 hours	4.0±0.7	17.6±6.80	10.5±4.1	94.9±30.2	2.55
FM 8 g every 8 hours	3.7±2.2	1,330±609	126±68	28.6±9.9	443.6

Note: Data presented as mean ± SD.

Abbreviations: AMK, amikacin; AUC, area under the plasma concentration–time curve; C_max, maximum plasma concentrations; CL, body clearance; COL, colistin; FM, fosfomycin; t1/2β, elimination half-life; PK, pharmacokinetics; V, volume of distribution.