Table 12.

Studies on combination between fosfomycin and tigecycline. CB: checkerboard assay; TK: time–kill assay; ET: E-test.

Strain	Year and Country	Author	Number of Isolates	Known Resistance Mechanisms or Determinants (%)	FOS-Resistant (%)	Tigecycline-Resistant (%)	In Vitro (Methods)/In Vivo (Animal and Site of Infection)	Synergistic Effect (%)	Additive Effect (%)	Indifferent Effect (%)	Antagonistic Effect (%)	FOS Susceptibility Restoration (%)	Tigecycline Susceptibility Restoration (%)	Comments	Reference
Enterobacterales	2019, USA	Flamm	20	7/30 MDR strains (A. baumannii, Enterobacterales e P. aeruginosa) included 2 ESBL e 2 KPC Enterobacterales	-	-	in vitro (CB)	5 (25%)	10 (50%)	5 (25%)	0%	-	-	Authors considered Partial Sinergy when FICI was between 0.5–1 and Additive effect for FICI = 1.	[38]
	2017, Taiwan	Ku	9	ESBL KP producing (100%)	4 (44,4%)	4 (44%)	in vitro (TK)	6 (66%)	0%	3 (33%)	0%	-	-	-	[84]
	2011, France	Berçot	9	NDM-1 KPC (100%)	2 (22%)	3 (33%)	in vitro (CB)	0%	-	9 (100%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4.	[85]
E. coli	2013, Switzerland	Corvec	1	Bj HDE-1 (100%) (ESBL and Ciprofloxacin resistant)	0%	0%	in vitro (TK); in vivo (Guinea pigs, cage infection)	TK: 0%; in vivo: 0%	TK: 100%; in vivo: 0%	TK: 0%; in vivo: 100%	0%	-	-	-	[73]
	2011, Greece	Samonis	20	ESBL (100%)	0%	1 (5%)	in vitro (ET)	5 (25%)	-	15 (75%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4. In vivo experiment: bacterial count using FOS + TIG combination was reduced ≥ 2 log over single antimicrobials	[86]
K. pneumoniae	2019, China	Huang	30	KPC (100%)	19 (63%)	11 (36%)	in vitro (ET, CB)	ET: 5 (16%); CK: 4 (13%)	ET: 9 (30%); CK: 11 (36%)	ETt: 16 (53%); CK: 15 (50%)	0%	ET: 14/19 (73%); CK: 6/15 (40%)	ET: 5/11 (45%); CK: 7/13 (53,%)	ET and CB showed different rates of FOS and TIG resistance and different rates of susceptibility restoration; otherwise the 2 methods had similar resulted in establishing synergistic, additive or indifferent effect.	[88]
	2019, Greece	Papoutsaki	11	KPC (100%)	35%	96%	in vitro (ET, TK)	ET: 16/33 (48%); TKA: 1/22 (4%)	ET: 17/33 (51%); TKA: 21/22 (95%)	0%	0%	-	-	ET was performed three times with different methods: a) Etest/Agar method; b) Cross formation method; c) MIC/MIC ratio method. TK was performed two times: a) TIG 1,3 mg/L + FOS 0,5xMIC and b) TIG 1,3 mg/L + FOS 30 mg/L.	[87]
	2017, China	Yu	136	KPC (100%)	78 (57%)	25 (18%)	in vitro (CB, TK)	CK: 2 (1%); TKA: 0%	CK: 113 (83%); TKA: 3 (75%)	CK: 19 (14%); TKA: 1 (25%)	CK: 2 (1%); TKA: 0%	-	-	Only 4 strains were tested with TK.	[89]
	2013, Turkey	Evren	12	OXA-48 (100%)	11 (92%)	5 (41%)	in vitro (CB)	4 (33%)	6 (50%)	2 (16%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4. In vivo experiment: bacterial count using FOS + TIG combination was reduced ≥ 2 log over single antimicrobials	[74]
	2011, Greece	Samonis	65	Serine-KPC (77%) - MBL (1%) - ESBL (21%)	1 (1%)	10 (15%)	in vitro (ET)	18 (27%)	-	47 (72%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4. In vivo experiment: bacterial count using FOS + TIG combination was reduced ≥ 2 log over single antimicrobials	[86]
P. aeruginosa	2011, Greece	Samonis	15	MDR (100%)	1 (6%)	15 (100%)	in vitro (ET)	2 (13%)	-	13 (86%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4. In vivo experiment: bacterial count using FOS + TIG combination was reduced ≥ 2 log over single antimicrobials	[86]
A. baumannii	2019, USA	Flamm	5	7/30 MDR strains (A. baumannii, Enterobacterales e P. aeruginosa)	-	-	in vitro (CB)	0%	4 (80%)	1 (20%)	0%	-	-	Authors considered Partial Sinergy when FICI was between 0.5–1 and Additive effect for FICI = 1.	[38]
	2016, Netherlands	Leite	20	Colistin-Resistant (65%)	20 (100%)	5%	in vitro (CB, 2-Well Method)	0%	-	-	-	-	-	Any synergistic effect was reported. Additive, Indifferent and antagonistic effect were not evaluated.	[83]
S. aureus	2018, Italy	Simonetti	15	MRSA (100%)	0	0%	in vitro (CB); in vivo (mice, wound infection)	12 (80%)	-	3 (20%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4. In vivo experiment: bacterial count using FOS + TIG combination was reduced ≥ 2 log over single antimicrobials.	[90]
	2012, Taiwan	Tang	33 (8 TK)	MRSA (100%)	6%	0%	in vitro (TK, Biofilm MTT-staining method)	0%	-	100%	0%	-	-	Only 8 strains were tested with Time–kill Assay. Biofilm cultures were 100% TIG resistant and 94% FOS resistant. No FICI were reported by authors, no synergistic effect was seen on any strains.	[69]
E. faecalis	2018, Italy	Simonetti	15	-	0%	0%	in vitro (CB); in vivo (mice, wound infection)	12 (80%)	-	3 (20%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4. In vivo experiment: bacterial count using FOS + TIG combination was reduced ≥ 2 log over single antimicrobials.	[90]
	2013, Taiwan	Tang	9	VRE (100%)	56%	0%	in vitro (TK, Biofilm Model)	TKA: 3 (33%); BM: 5 (56%)	-	-	-	-	-	Additive, Indifferent and antagonistic effect were not evaluated.	[13]
E. faecium	2019, Thailand	Hemapampairoa	12	VRE (100%)	12 (100%)	3 (25%)	in vitro (CB)	1 (8%)	9 (75%)	2 (16)%	0%	-	-	-	[55]
	2018, Italy	Simonetti	15	-	0%	0%	in vitro (CB)	10 (66)%	-	5 (33%)	0%	-	-	Authors considered Indifferent effect for FICI between 0.5 and 4.	[90]
	2013, Taiwan	Tang	10	VRE (100%)	70%	0%	in vitro (TK, Biofilm Model)	TKA: 3 (30%); BM: 1 (10%)	-	-	-	-	-	Additive, Indifferent and antagonistic effect were not evaluated.	[13]
N. gonorrhoeae	2015, Netherlands	Wind	4	Azithromycin and Ceftriaxone Resistant (100%)	-	-	in vitro (ET)	0%	0%	4 (100%)	-	-	-	-	[54]