Comparative Activities of Tigecycline and Other Tetracyclines against Nonfermenting Gram-Negative Bacilli, Excluding Acinetobacter spp.

LETTER

Tigecycline, a glycylcycline, is a semisynthetic derivative of minocycline with a broad spectrum of activity against aerobic and anaerobic bacteria (2, 12, 16).

In the literature there are several publications concerning tigecycline activity, most of them related to Acinetobacter baumannii and Stenotrophomonas maltophilia isolates (1, 5, 8, 10, 11, 14); however, its activity against other species of nonfermenting Gram-negative bacilli (NFGNB) has rarely been reported.

Here we determined the activities of tetracycline, doxycycline, minocycline, and tigecycline against 195 clinical isolates of NFGNB (excluding Acinetobacter spp.) recovered from clinical materials of patients treated at the Hospital de Clínicas Jose de San Martin, Universidad de Buenos Aires, Argentina, during the 1995–2009 period. Only one isolate per patient was included in the study.

All the isolates were identified using standard biochemical tests (15) and API 20NE (bioMérieux, Marcy l'Etoile, France). PCR amplification of the 16S rRNA was performed in order to identify Burkholderia cepacia complex, Burkholderia gladioli, Pandoraea spp., Inquilinus limosus, and Bordetella hinzii using the primers described by Weisburg et al. (17).

Susceptibility was determined by agar dilution (Mueller-Hinton agar was from Difco, BBL) according to the Clinical and Laboratory Standards Institute (CLSI) recommendations (3). MIC determination for tigecycline and the other tetracyclines was performed using freshly prepared agar with the antibiotic incorporated into the medium on the day of use and inoculated within a few hours.

Control strains for the agar dilution test included Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213, and Enterococcus faecalis ATCC 29212.

Drug powders were obtained commercially or provided by their respective manufacturers.

The MIC breakpoints for tetracycline, doxycycline, and minocycline were interpreted using CLSI categories (4) for other non-Enterobacteriaceae: susceptibility at 4 μg/ml, intermediacy at 8 μg/ml, and resistance at 16 μg/ml. In addition, those recommended by CLSI for Burkholderia cepacia and for Stenotrophomonas maltophilia for minocycline (susceptibility at 4 μg/ml, intermediacy at 8 μg/ml, and resistance at 16 μg/ml) and those recommended by the U.S. Food and Drug Administration (FDA) when testing Enterobacteriaceae (susceptibility at 2 μg/ml, intermediacy at 4 μg/ml, and resistance at 8 μg/ml) for tigecycline were used.

MIC₅₀ and MIC₉₀ values, together with the MIC ranges of NFGNB isolates, are shown in Tables 1 and 2.

Table 1.

In vitro susceptibilities of 138 commonly isolated nonfermenting Gram-negative bacillus isolates to tigecycline and other tetracyclines

Species (no. of isolates)	Drug	MIC (μg/ml)
		Range	Breakpoint interpretationa			MIC50	MIC90
			S	I	R
Achromobacter spp. (33)	Tetracycline	2–256	≤4	8	≥16	256	256
	Doxycycline	0.5–64	≤4	8	≥16	16	64
	Minocycline	0.5–16	≤4	8	≥16	2	8
	Tigecyclineb	0.5–4	≤2	4	≥8	2	4
Alcaligenes faecalis (11)	Tetracycline	4–32	≤4	8	≥16	8	16
	Doxycycline	2–16	≤4	8	≥16	2	8
	Minocycline	1–8	≤4	8	≥16	2	8
	Tigecyclineb	1–8	≤2	4	≥8	2	4
Burkholderia cepacia complex (21)	Tetracycline	0.03–256	≤4	8	≥16	16	64
	Doxycycline	0.06–16	≤4	8	≥16	4	4
	Minocyclinec	0.03–4	≤4	8	≥16	1	2
	Tigecyclineb	0.03–2	≤2	4	≥8	0.5	2
Chryseobacterium gleum-indologenes (11)	Tetracycline	0.06–32	≤4	8	≥16	8	32
	Doxycycline	0.125–16	≤4	8	≥16	1	8
	Minocycline	0.03–2	≤4	8	≥16	0.25	1
	Tigecyclineb	0.03–4	≤2	4	≥8	1	4
Elizabethkingia meningoseptica (15)	Tetracycline	2–128	≤4	8	≥16	32	64
	Doxycycline	1–32	≤4	8	≥16	2	4
	Minocycline	0.06–2	≤4	8	≥16	0.25	0.5
	Tigecyclineb	0.25–8	≤2	4	≥8	2	8
Stenotrophomonas maltophilia (26)	Tetracycline	0.5–64	≤4	8	≥16	8	16
	Doxycycline	1–4	≤4	8	≥16	2	2
	Minocyclined	0.25–2	≤4	8	≥16	0.25	0.5
	Tigecyclineb	0.125–8	≤2	4	≥8	0.5	2
Pseudomonas putida (11)	Tetracycline	0.125–256	≤4	8	≥16	2	16
	Doxycycline	0.06–128	≤4	8	≥16	4	32
	Minocycline	0.06–32	≤4	8	≥16	2	16
	Tigecyclineb	0.25–16	≤2	4	≥8	2	8
Pseudomonas stutzeri group (10)	Tetracycline	0.125–8	≤4	8	≥16	0.5	4
	Doxycycline	0.25–8	≤4	8	≥16	2	8
	Minocycline	0.5–8	≤4	8	≥16	1	4
	Tigecyclineb	0.06–4	≤2	4	≥8	0.25	2

^aS, sensitive; I, intermediate; R, resistant. CLSI categories for other non-Enterobacteriaceae for tetracycline, doxycycline, and minocycline were used (susceptibility at 4 μg/ml, intermediacy at 8 μg/ml, and resistance at 16 μg/ml).

^bBreakpoint recommended by the U.S. Food and Drug Administration when testing Enterobacteriaceae for tigecycline (susceptibility at 2 μg/ml, intermediacy at 4 μg/ml, and resistance at 8 μg/ml).

^cBurkholderia cepacia CLSI breakpoint recommended for minocycline.

^dStenotrophomonas maltophilia CLSI breakpoint recommended for minocycline.

Table 2.

In vitro susceptibilities of 57 uncommonly isolated nonfermenting Gram-negative bacillus isolates to tigecycline and other tetracyclines

Species	No. of isolates	MIC range (μg/ml)
		Tetracycline	Doxycycline	Minocycline	Tigecycline
Rhizobium radiobacter	5	0.25–4	0.25–0.5	0.06–0.5	0.5–0.5
Ochrobactrum anthropi	8	0.5–16	0.06–8	≤0.03–2	0.25–2
Burkholderia gladioli	2	4–64	2–4	1–4	1–2
Bordetella bronchiseptica	3	0.5–0.5	0.25–0.25	0.25–0.25	0.25–0.25
Bordetella hinzii	3	0.5–4	0.25–1	0.25–0.5	0.25–0.5
Delftia acidovorans	3	0.5–2	0.125–0.25	0.06–0.25	0.125–0.5
Pseudomonas oryzihabitans	6	0.5–4	0.25–4	0.25–4	≤0.03–4
Pseudomonas pseudoalcaligenes	3	0.5–4	2–4	2–4	0.25–1
Shewanella algae	5	0.25–1	0.25–1	0.06–0.25	0.125–0.5
Sphingomonas paucimobilis	7	0.25–4	0.125–1	<0.03–0.06	0.25–1
Sphingobacterium multivorum	2	2–4	1–2	0.06–0.25	0.25–0.25
Myroides spp.	5	2–128	0.5–16	0.06–0.5	0.5–4
Pandoraea spp.a	4	4–128	1–64	1–16	2–32
Inquilinus limosus	1	128	16	2	0.5

^aP. pnomenusa (n = 1), P. apista (n = 1), P. pulmonicola (n = 1), and P. sputorum (n = 1).

Tigecycline was active against most species tested. Also, it was more active than minocycline against Pseudomonas pseudoalcaligenes, the Pseudomonas stutzeri group, and Pseudomonas oryzihabitans. However, its activity was lower than that of minocycline against members of the Flavobacteriaceae (Elizabethkingia meningoseptica and Chryseobacterium gleum-indologenes) and Myroideaceae families and against S. maltophilia. The observed behavior against S. maltophilia has also been reported by other authors (1, 11, 13). In addition, the MIC₉₀ for tigecycline (MIC₉₀, 2 μg/ml) was slightly lower than that previously reported by other authors (1, 6, 7, 13) and in agreement with those reported by Milatovic et al. (11).

Concerning the activity of tigecycline against E. meningoseptica isolates, our results (MIC₉₀, 8 μg/ml) differ from those reported by Lin et al., who obtained 88.5% sensitivity against isolates tested (MIC₉₀, 3 μg/ml) (9). However, this discrepancy could be attributed to the different assessment methods of antimicrobial susceptibility used in the two cases.

None of the tetracyclines tested were active against Pseudomonas putida, and all had weak activity against Achromobacter spp. and Alcaligenes faecalis.

The lowest MIC values for tigecycline were observed against Shewanella algae, Sphingomonas paucimobilis, Delftia acidovorans, Rhizobium radiobacter, Pseudomonas oryzihabitans, and Bordetella species.

Regarding Burkholderia cepacia complex isolates, minocycline and tigecycline had comparable activities (MIC₉₀, 2 μg/ml), and in contrast to the report by Milatovic et al. (11), 100% of isolates assayed in the present study were susceptible to both antibiotics; however, our work, like the others, does not report which Burkholderia cepacia complex genomovars were included in both studies.

Our results indicate that tigecycline could be a therapeutic option for the treatment of nonfermenting Gram-negative bacillus infections in view of the multidrug resistance observed in several species.