Evaluation of Synergistic Effect of Combined Multidrug-Resistant Acinetobacter baumannii Treatment with Linalool and Colistin on to Expand Candidate for Therapeutic Option

Ung-Jun Kim; Choon-Mee Kim; Sook-Jin Jang; Seul-Bi Lee; Seong-Sik Cho; Seok-Hoon Jeong; Young-Jin Ko; Seong-Ho Kang; Geon Park; Na-Ra Yoon; hoon Lim; Joong-Ki Kook

doi:10.5145/ACM.2020.23.1.1

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Kim, Kim, Jang, Lee, Cho, Jeong, Ko, Kang, Park, Yoon, Lim, and Kook: Evaluation of Synergistic Effect of Combined Multidrug-Resistant Acinetobacter baumannii Treatment with Linalool and Colistin on to Expand Candidate for Therapeutic Option

Original Article

Ann Clin Microbiol 2020;23(1):11-20.

Published online: 12 March 2020

DOI: https://doi.org/10.5145/ACM.2020.23.1.1

Evaluation of Synergistic Effect of Combined Multidrug-Resistant Acinetobacter baumannii Treatment with Linalool and Colistin on to Expand Candidate for Therapeutic Option

Ung-Jun Kim¹, Choon-Mee Kim², Sook-Jin Jang¹, Seul-Bi Lee¹, Seong-Sik Cho¹, Seok-Hoon Jeong³, Young-Jin Ko¹, Seong-Ho Kang¹, Geon Park¹, Na-Ra Yoon⁴, hoon Lim⁶, Joong-Ki Kook⁷

¹Department of Laboratory Medicine, Chosun University, Gwangju

²Premedical Science, College of Medicine, Chosun University, Gwangju

³Department of Laboratory Medicine and Research Institute of Antimicrobial Resistance, Yonsei University College of Medicine, Seoul

⁴Department of Internal Medicine, Chosun University, Gwang-Ju, Republic of Korea

⁵Department of Medical Education, Chosun University, Gwang-Ju, Republic of Korea

⁶Department of Urology, College of Medicine, Chosun University, Gwangju

⁷Korean Collection for Oral Microbiology and Department of Oral Biochemistry, College of Dentistry, Chosun University, Gwang-Ju, Republic of Korea

Corresponding author Sook-Jin Jang E-mail: sjbjang@chosun.ac.kr Tel: +82-62-220-3259 Fax: +82-62-232-2063

Received 29 May 2019 Revised 11 September 2019 Accepted 11 September 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Acinetobacter baumannii infection is a significant health problem worldwide due to increased drug resistance. The limited antimicrobial alternatives for the treatment of severe infections by multidrug-resistant A. baumannii (MDRAB) make the search for other therapeutic options more urgent. Linalool, the major oil compound in Coriandrum sativum, was recently found to have high antibacterial activity against A. baumannii. The purpose of this study was to investigate the synergistic effect of linalool and colistin combinations against MDRAB and extensively drug-resistant A. baumannii (XDRAB).

Methods

A total of 51 strains of A. baumannii clincal isolates, consisting of 10 MDRAB and 41 XDRAB were tested. We determined the minimum inhibitory concentration (MIC) of linalool for the test strains using the broth microdilution method and searched for interactions using the time-kill assay.

Results

The time-kill assay showed that the linalool and colistin combination displayed a high rate of synergy (92.1%) (by synergy criteria 2), low rate of indifference (7.8%), and a high rate of bactericidal activity (74.5%) in the 51 clinical isolates of A. baumannii. The synergy ^rates for the linalool and colistin combination against MDRAB and XDRAB were 96% and 92.1%, respectively. No antagonism was observed for the linalool and colistin combination.

Conclusions

The combination of linalool and colistin showed a high synergy rate, which may be beneficial for controlling MDRAB infections. Therefore, this combination is a good candidate for in vivo studies to assess its efficacy in the treatment of MDRAB infections.

Keywords: Acinetobacter baumannii, Colistin, Linalool, Synergy, Time-kill assay

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Table 1.

Results of time-kill assay and bactericidality against two-drug combinations of linalool and colistin of 10 MDR and 41 XDR clinical isolates of A. baumannii

Group	Isolate	Log10(VCC of combination/ VCC of MASA) of 24 hr	Log10(VCC of 24 hr) – Log10(VCC of 0 hr)			Synergy criteria 1‡	Synergy criteria 2§	MIC	MIC C	Category	Bactericidality∥
Group	Isolate	Log10(VCC of combination/ VCC of MASA) of 24 hr	LNL*	CST†	LNL* + CST†	Synergy criteria 1‡	Synergy criteria 2§	LNL	CST	CST	LNL*	CST† L	NL* + CST†
MDR	89–92	–5.2	3.8	3.7	–1.4	S	I ¶	4.0	8.0	R	N	N	N
	171–84	–6.1	0.1	2.9	–5.8	S	S	16.0	2.0	S	N	N	B
	172–91	–3.4	0.8	0.8	–2.5	S	S	16.0	2.0	S	N	N	N
	172–99	–5.1	–1.1	2.0	–6.2	S	S	4.0	1.0	S	N	N	B
	174–99	–8.1	2.9	3.1	–5.2	S	S	16.0	16.0	R	N	N	B
	180–82	–2.7	–3.4	0.1	–5.9	S	S	16.0	0.5	S	B	N	B
	181–67	–9.5	1.9	1.7	–5.3	S	S	32.0	0.5	S	N	N	B
	186–88	–5.0	–0.3	0.9	–5.2	S	S	16.0	2.0	S	N	N	B
	191–19	–8.2	3.1	4.2	–5.0	S	S	8.0	2.0	S	N	N	B
	200–92	–7.4	2.1	4.1	–5.1	S	S	8.0	2.0	S	N	N	B
XDR	69–84	–5.2	2.6	3.9	–2.5	S	S	4.0	8.0	R	N	N	N
	99–73	–6.1	0.2	0.3	–5.3	S	S	8.0	8.0	R	N	N	B
	111–27	–6.2	0.9	2.8	–5.3	S	S	32.0	2.0	S	N	N	B
	130–33	–4.1	1.8	1.9	–2.3	S	S	4.0	16.0	R	N	N	N
	139–27	–4.0	–1.3	3.1	–5.3	S	S	16.0	2.0	S	N	N	B
	148–33	–4.4	–1.4	1.3	–5.8	S	S	8.0	8.0	R	N	N	B
	150–94	–5.4	2.2	2.1	–3.2	S	S	8.0	2.0	S	N	N	B
	155–24	–2.7	1.8	3.6	–2.7	S	S	4.0	2.0	S	N	N	N
	158–46	–4.0	–1.9	–1.9	–5.9	S	S	8.0	2.0	S	N	N	B
	158–86	–7.2	2.2	3.2	–5.0	S	S	8.0	1.0	S	N	N	B
	158–86158–87	−7.2 −5.8	2.2 0.7	3.2 4.2	−5.0 −5.2	S S	S S	8.0 8.0	1.0 8.0	S R	N N	N N	B B
	159–86	–7.0	1.0	3.2	–6.0	S	S	8.0	0.3	S	N	N	B
	160–14	–2.4	–0.2	–0.3	–2.6	S	S	4.0	16.0	R	N	N	N
	160–15	–7.0	1.7	1.7	–5.2	S	S	16.0	1.0	S	N	N	B
	160–68	–6.0	0.7	3.9	–4.9	S	S	16.0	8.0	R	N	N	B
	160–92	–6.2	0.9	3.8	–5.3	S	S	16.0	4.0	R	N	N	B
	160–93	–3.2	–3.0	1.9	–6.0	S	S	8.0	8.0	R	N	N	B
	162–83	–6.0	–0.2	2.3	–5.9	S	S	16.0	0.5	S	N	N	B
	162–88	–3.1	0.7	3.8	–2.3	S	S	4.0	8.0	R	N	N	N
	163–71	–3.6	4.4	4.3	0.8	S	I	2.0	8.0	R	N	N	N
	163–72	–1.9	–0.5	0.7	–2.5	I	I	4.0	8.0	R	N	N	N
	163–77	–7.3	2.2	2.0	–5.1	S	S	16.0	4.0	R	N	N	B
	164–35	–4.3	1.8	1.9	–2.3	S	S	4.0	2.0	S	N	N	N
	164–62	–5.8	0.6	4.0	–5.0	S	S	8.0	2.0	S	N	N	B
	165–41	–3.3	0.8	1.7	–2.4	S	S	4.0	8.0	R	N	N	N
	165–83	–8.2	2.9	2.9	–5.2	S	S	16.0	8.0	R	N	N	B
	165–83	–7.2	1.8	2.8	–5.2	S	S	16.0	8.0	R	N	N	B
	166–13	–6.4	2.0	2.9	–4.4	S	S	16.0	0.5	S	N	N	B
	166–24	–6.2	0.9	3.0	–5.3	S	S	8.0	1.0	S	N	N	B
	166–61	–8.3	3.5	4.3	–4.8	S	S	32.0	1.0	S	N	N	B
	172–89	–8.2	2.4	2.3	–6.0	S	S	8.0	2.0	S	N	N	B
	177–35	–5.2	2.9	2.9	–2.1	S	S	4.0	2.0	S	N	N	N
	189–52	–7.2	2.1	3.2	–4.9	S	S	8.0	2.0	S	N	N	B
	189–97	–7.1	1.8	1.9	–5.2	S	S	16.0	2.0	S	N	N	B
	200–19	–4.3	2.0	2.0	–2.2	S	S	8.0	2.0	S	N	N	N
	200–19218–62	−4.3 −6.0	2.0 0.8	2.0 0.6	−2.2 −5.2	S S	S S	8.0 16.0	2.0 1.0	S S	N N	N N	N B
	219–12	–5.3	2.1	1.9	–3.2	S	S	16.0	1.0	S	N	N	B
	219–12219–56	−5.3 −6.9	2.1 1.7	1.9 3.0	−3.2 −5.0	S S	S S	16.0 16.0	1.0 1.0	S S	N N	N N	B B
	219–67	–0.4	–4.0	4.0	–4.4	I	I	16.0	1.0	S	B	N	B
	222–23	–2.8	–3.2	1.1	–6.1	S	S	8.0	1.0	S	B	N	B
	230–54	–5.0	–1.1	–1.0	–6.1	S	S	8.0	1.0	S	N	N	B

*Linalool 1/4 MIC; †Colistin 2 μg/mL; ‡≥2 log₁₀ CFU/mL reduction with the combination compared with the most active single agent of 24hr; §≥2 log₁₀ CFU/mL reduction with the combination compared with the most active single agent and ≥2 log₁₀ CFU/mL reduction below the initial inoculum at 24 hr; ∥≥3 log₁₀ CFU/mL reduction compared with the initial inoculums; ¶ <2 log₁₀ change in CFU/mL at 24 hr with the combination compared with the most active single agent Abbreviation: MIC, minimum inhibitory concentration; LNL, Linalool; CST, Colistin; B, bactericidal; N, non-bactericidal; MDR, multidrug-resistant; XDR, extensively drug-resistant; S, synergy; I, Indifference; VCC, viable cell count, MASA, most active single agent.

Table 2.

Comparison of time-kill assay results between MDR and XDR groups against combination of colistin and linalool

Combination of antibiotics	Interaction	MDR	XDR	Total
Combination of antibiotics	Interaction	No. (%)	No. (%)	No. (%)
Colistin+Linalool	Synergy (criteria 1)	10 (100)	39 (95.1)	49 (96.0)
	Synergy (criteria 2)	9 (90.0)	38 (92.6)	47 (92.1)
	Indifference	1 (10.0)	3 (7.3)	4 (7.8)
	Antagonism Bactericidal	0 (0) 8 (80.0)	0 (0) 30 (73.1)	0 (0) 38 (74.5)

Abbreviation: MDR, multidrug-resistant; XDR, extensively drug-resistant.

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