- Email: [email protected]
Reversal of meticillin resistance in Staphylococcus aureus by the anthelmintic avermectin
International Journal of Antimicrobial Agents 44 (2014) 274–279
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Letters to the Editor
Reversal of meticillin resistance in Staphylococcus aureus by the anthelmintic avermectin Sir, Pathogens have evolved to develop resistance to antibiotics readily and rapidly, regardless of continuous efforts in the development of new-generation antibiotics. One of the most notable examples is meticillin-resistant Staphylococcus aureus (MRSA), which developed resistance to meticillin (MET) only 2 years after its clinical introduction and has become one of the leading public health threats during recent decades [1]. Moreover, this pattern has held true among newly developed antimicrobials, leading to the emergence and prevalence of multidrug-resistant bacteria. To break the vicious circle of antibiotic resistance, it is critical to develop innovative drugs with novel modes of action that are unlikely to contribute to the increasing antibiotic resistance. While considering the costly and time-consuming pipeline of new drug development, an appealing and pragmatic approach is to synergistically screen a previously approved chemical library for new tricks of old drugs [2]. In the course of a synergistic screen, we identified for the first time that avermectin B1a (AVM) could act synergistically with MET to kill MRSA, rendering the bacteria once again vulnerable to MET. The avermectins were isolated from Streptomyces avermitilis during the 1970s and have been widely used as biopesticides [3]. Members of the avermectin family have also been approved as anthelmintic drugs for livestock or human use [3]. Recently, four members of the avermectin family were reported to selectively kill Mycobacterium tuberculosis [4]. Here we reported the MET resistance reversal effect of AVM, another member of the avermectin family. Individual minimum inhibitory concentrations (MICs) of AVM and MET were determined against a set of 35 MRSA clinical isolates by broth microdilution assay in cation-adjusted Mueller–Hinton broth following Clinical and Laboratory Standards Institute (CLSI) guideline M07-A8. The type strain S. aureus ATCC 6538 was also included as a meticillin-sensitive S. aureus (MSSA) control. The susceptibility results of 35 MRSA isolates and 1 MSSA to AVM and MET alone and in combination are summarised in Table 1. Consistent with the hospital records, all of the MRSA isolates were resistant to MET (MICs > 100 mg/L) and the MSSA strain was sensitive to MET (MIC = 0.78 mg/L). The MSSA strain and 14 of the 35 clinical MRSA isolates showed moderate susceptibility to AVM alone, with MICs ranging from 6.25 mg/L to 50 mg/L, whilst the others were inherently resistant to AVM (MICs > 100 mg/L). To identify the combination effect of AVM and MET, fractional inhibitory concentration indexes (FICIs) were estimated by the checkerboard assay. Of the 35 clinical MRSA isolates, 30 were
susceptible to the combination with FICIs < 0.5, with 5 others susceptible only to AVM (Table 1). Moreover, it was noteworthy that 21 of these 30 synergy-positive MRSA isolates were resistant to both AVM and MET when treated alone, suggesting a strong synergistic effect. Interestingly, it appeared that AVM could only restore the MET susceptibility in the MRSA isolates, whilst not improving MET efficacy towards the MSSA strain. This phenomenon indicated that the synergism was achieved by re-sensitising MRSA, possibly through interfering with the underlying MET resistance mechanisms that exist only in MRSA. To determine the antimicrobial actions of AVM alone and its combination with MET, four randomly selected MRSA isolates together with the MSSA strain were tested for their survival kinetics following drug treatment (Supplementary Fig. S1). In the AVMtreated group, replication both of MSSA and MRSA isolates was only suppressed by AVM even at 8× MIC, suggesting that AVM alone was bacteriostatic (Supplementary Fig. S1A). In the combination treated group, isolates 19878 and 19976 were steadily killed over time, with ca. 2 log10 decrease in CFU/mL within 12 h, exhibiting a potent bactericidal action (Supplementary Fig. S1B). The combination effects of AVM with other antimicrobials on MRSA were also tested and no synergism or antagonism was detected (data not shown). To our knowledge, this is the first report describing the antistaphylococcal activity of AVM and its bactericidal synergy with MET especially against MRSA. The effect was so pronounced that clinical isolates of MRSA regained sensitivity to MET, which they were previously able to beat, enabling use again of this wellestablished antibiotic against this resistant pathogen. Considering the well-established safety profiles of AVM, we suggest that it could be repurposed as a MET sensitiser for MRSA treatment. The mechanism of MET resistance in MRSA involves the acquisition of foreign genetic elements encoding penicillin-binding protein 2a (PBP2a), which is refractory to inhibition by current -lactam antibiotics while retaining glycosyltransferase and transpeptidase activities [5]. Since the synergistic effect could only be observed among MRSA isolates, it would be worth investigating whether AVM reverses the MET resistance by acting on PBP2a or its transcriptional regulation. This work also proved that ‘drug repurposing’ and ‘drug combination’ could be efficient ways to develop new antibiotics and to overcome drug resistance. Future study is underway to investigate the mechanism of synergy between AVM and MET and to test for their therapeutic efficacy in animal models. Funding: This work was supported in part by grants from the National Natural Science Foundation of China [812111049, 31320103911 and 31125002] and the Ministry of Science and Technology of the People’s Republic of China [2011ZX11102-011-11]. LZ is an awardee for the National Distinguished Young Scholar Program in China.
0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Letters to the Editor / International Journal of Antimicrobial Agents 44 (2014) 274–279
275
Table 1 In vitro inhibitory activity of avermectin (AVM) and its combination with meticillin (MET) against MET-resistant Staphylococcus aureus (MRSA) and MET-sensitive S. aureus (MSSA). Isolate
MRSA isolates 18466 18475 18534 18558 18567 18625 18786 18878 18908 19046 19048 19102 19156 19161 19177 19423 19491 19494 19498 19554 19613 19655 19806 19877 19878 19900 19916 19952 19976 MRSA-A 306-642 306-8-24 309-6 309-7 309-8 ATCC 6538d
Sourcea
CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY 306 306 309 309 309 ATCC
In vitro MIC (mg/L) AVM
MET
VAN
AVM + MET combination
12.5 >100 >100 25 25 25 25 >100 25 >100 >100 >100 >100 >100 25 >100 >100 >100 >100 >100 25 >100 >100 >100 25 >100 25 >100 >100 >100 >100 25 6.25 50 50 25
>100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 0.78
0.5 1 1 0.5 0.5 0.5 1 1 0.5 1 1 1 1 1 0.5 1 1 1 1 1 1 1 1 1 0.5 1 1 0.5 1 1 1 0.5 0.5 1 1 1
12.5/–c 25/25 25/12.5 6.25/25 6.25/12.5 25/– 6.25/25 25/0.39 25/– 25/1.56 25/6.25 12.5/12.5 25/1.56 25/12.5 6.25/25 25/6.25 12.5/1.56 12.5/6.25 25/3.125 25/6.25 6.25/25 25/0.78 25/12.5 25/3.125 6.25/25 25/6.25 25/– 12.5/3.125 12.5/3.125 12.5/12.5 12.5/25 6.25/25 6.25/– 12.5/6.25 12.5/6.25 25/– or –/0.78
FICI
Synergyb
>1 <0.5 <0.38 <0.5 <0.38 >1 <0.5 <0.25 >1 <0.27 <0.31 <0.25 <0.27 <0.38 <0.5 <0.31 <0.14 <0.19 <0.28 <0.31 <0.5 <0.26 <0.38 <0.28 <0.5 <0.31 >1 <0.16 <0.16 <0.25 <0.38 <0.5 >1 <0.31 <0.31 >1
N Y Y Y Y N Y Y N Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N Y Y Y Y Y N Y Y N
MIC, minimum inhibitory concentration; VAN, vancomycin; FICI, fractional inhibitory concentration index. a CY, Beijing Chao-Yang Hospital (Beijing, China); 306, The 306th Hospital of People’s Liberation Army (Beijing, China); 309, The 309th Hospital of People’s Liberation Army (Beijing, China). b N, non-synergistic activity; Y, synergistic activity. c –, no contribution to the activity of the combination. d MSSA type strain.
Competing interests: None declared. Ethical approval: Not required. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijantimicag. 2014.05.002. References [1] Barber M. Methicillin-resistant staphylococci. J Clin Pathol 1961;14:385–93. [2] Chong CR, Sullivan Jr DJ. New uses for old drugs. Nature 2007;448:645–6. [3] Campbell WC. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol 2012;13:853–65. [4] Lim LE, Vilchèze C, Ng C, Jacobs Jr WR, Ramón-García S, Thompson CJ. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob Agents Chemother 2013;57: 1040–6. [5] Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog 2002;85:57–72.
Hui Guo a,b,1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China b University of Chinese Academy of Sciences, Beijing 100049, PR China a
Biao Ren 1 Huanqin Dai ∗∗ Shengwang Dai 2 Yuhan Zhang 3 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China Yingmei Liu Bin Cao Beijing Chao-Yang Hospital, Beijing 100020, PR China Lixin Zhang ∗ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China
276
Letters to the Editor / International Journal of Antimicrobial Agents 44 (2014) 274–279 ∗∗ Corresponding
author.
∗ Corresponding author. Present address: Room F816, IMCAS, 1st Beichen West Road, Chaoyang District, Beijing 100101, PR China. Tel.: +86 10 6480 7665; fax: +86 10 6480 7665. E-mail addresses: [email protected] (H. Dai), [email protected] (L. Zhang). 1 2
These two authors contributed equally to this work.
Present address: Beihang University, Beijing 100191, PR China. 3
Present address: Georgetown University Medical Center, Washington, DC 20057, USA. 6 May 2014
http://dx.doi.org/10.1016/j.ijantimicag.2014.05.002
In vitro antimicrobial oxazolidinone tedizolid against Staphylococcus resistant Gram-positive tre study in China
activity of the novel and comparator agents aureus and linezolidpathogens: a multicen-
Sir, Tedizolid, a novel oxazolidinone, acts by inhibiting protein synthesis and has broad activity against Gram-positive pathogens, including strains that are resistant to linezolid [1]. Our previous study indicated that linezolid-resistant coagulase-negative staphylococci (CoNS) and enterococci have emerged in several cities across China, causing serious concern for clinicians. Although several studies have addressed the antibacterial activity of tedizolid against Gram-positive bacteria, this study is the first to provide a specific overview of tedizolid activity in China based on a multicentre study. In total, 100 non-duplicate meticillin-resistant Staphylococcus aureus (MRSA), 100 meticillin-sensitive S. aureus (MSSA), 43 linezolid-resistant CoNS and 17 linezolid-resistant enterococci isolates were collected from 16 teaching hospitals across China from 2009 to 2013. One-half of the S. aureus isolates were recovered from skin and soft-tissue infections and the other half
were recovered from lower respiratory tract infections. Of the 43 linezolid-resistant CoNS isolates, 42 (97.7%) were recovered from bacteraemia and 1 (2.3%) was recovered from a urinary tract infection (UTI). Among the 17 linezolid-resistant enterococci, 7 isolates (41.2%) were recovered from wound infections, 7 (41.2%) were recovered from UTIs and 3 (17.6%) were recovered from bacteraemia. Minimum inhibitory concentration (MIC) data for each antibiotic were determined using the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Of the 200 S. aureus strains, including 100 MRSA and 100 MSSA, tedizolid, vancomycin, daptomycin, tigecycline and linezolid were the most active agents (100% effective). For the 100 MRSA isolates, the MIC50 and MIC90 values (MIC required to inhibit 50% and 90% of the isolates, respectively) for tedizolid were both 0.25 mg/L, whilst these two values were 2 mg/L for linezolid (Table 1). For the 100 MSSA isolates, the MIC50 and MIC90 values for tedizolid were 0.25 mg/L and 0.5 mg/L, respectively, whilst both values were 2 mg/L for linezolid. The distribution peaks for tedizolid and linezolid MICs were 0.25 mg/L and 2 mg/L, respectively, indicating that the potency of tedizolid against S. aureus was eightfold greater than it was for linezolid. The tedizolid MICs of 99% of the S. aureus strains were ≤0.5 mg/L. In another study, tedizolid exhibited 4- to 16fold greater activity than linezolid against Gram-positive species, including MRSA [2]. All CoNS included in this study were resistant to meticillin and linezolid, and all were multiresistant. Vancomycin, daptomycin and tigecycline were the most active agents against all of the isolates (100% effective). For the 43 linezolid-resistant CoNS isolates, the MIC50 and MIC90 values for tedizolid were 2 mg/L and 4 mg/L, respectively, whilst these values were 256 mg/L and >256 mg/L, respectively, for linezolid (Table 1). Both the MIC50 and MIC90 for tedizolid against CoNS were ≥64-fold lower than for linezolid. Of the 43 linezolid-resistant CoNS isolates, 38 (88.4%) harboured the multidrug resistance gene cfr and 31 (72.1%) had the G2576T mutation in the 23S rRNA gene; 26 (60.5%) had both the cfr gene and the G2576T mutation. CoNS with cfr and/or the G2576T mutation in the 23S rRNA gene had a high MIC (8 mg/L to >256 mg/L) for linezolid, whilst tedizolid retained high antimicrobial activity
Table 1 Antimicrobial activities of tedizolid and linezolid against Staphylococcus aureus, coagulase-negative staphylococci (CoNS) and enterococci isolates. Antimicrobial agent/phenotype
N
MIC (mg/L) MIC50
Tedizolid All S. aureus MSSA MRSA All linezolid-resistant CoNS CoNS with cfr gene and G2576T mutation CoNS with only cfr gene CoNS with only G2576T mutation Linezolid-resistant enterococci Linezolid All S. aureus MSSA MRSA All linezolid-resistant CoNS CoNS with cfr gene and G2576T mutation CoNS with only cfr gene CoNS with only G2576T mutation Linezolid-resistant enterococci
200 100 100 43 26 12 5 17 200 100 100 43 26 12 5 17
0.25 0.25 0.25 2 2 2 2 0.5 2 2 2 256 256 >256 16 8
MIC90 0.5 0.5 0.25 4 4 4 2 1 2 2 2 >256 >256 >256 256 16
Range 0.064–1 0.125–1 0.064–1 0.12–4 0.5–4 0.12–4 1–2 0.5–2 0.25–4 1–2 0.25–4 8 to >256 8 to >256 8 to >256 8–256 8–16
MIC, minimum inhibitory concentration; MIC50/90 , MIC required to inhibit 50% and 90% of the isolates, respectively; MSSA, meticillin-sensitive S. aureus; MRSA, meticillinresistant S. aureus.
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Letters to the Editor
Reversal of meticillin resistance in Staphylococcus aureus by the anthelmintic avermectin Sir, Pathogens have evolved to develop resistance to antibiotics readily and rapidly, regardless of continuous efforts in the development of new-generation antibiotics. One of the most notable examples is meticillin-resistant Staphylococcus aureus (MRSA), which developed resistance to meticillin (MET) only 2 years after its clinical introduction and has become one of the leading public health threats during recent decades [1]. Moreover, this pattern has held true among newly developed antimicrobials, leading to the emergence and prevalence of multidrug-resistant bacteria. To break the vicious circle of antibiotic resistance, it is critical to develop innovative drugs with novel modes of action that are unlikely to contribute to the increasing antibiotic resistance. While considering the costly and time-consuming pipeline of new drug development, an appealing and pragmatic approach is to synergistically screen a previously approved chemical library for new tricks of old drugs [2]. In the course of a synergistic screen, we identified for the first time that avermectin B1a (AVM) could act synergistically with MET to kill MRSA, rendering the bacteria once again vulnerable to MET. The avermectins were isolated from Streptomyces avermitilis during the 1970s and have been widely used as biopesticides [3]. Members of the avermectin family have also been approved as anthelmintic drugs for livestock or human use [3]. Recently, four members of the avermectin family were reported to selectively kill Mycobacterium tuberculosis [4]. Here we reported the MET resistance reversal effect of AVM, another member of the avermectin family. Individual minimum inhibitory concentrations (MICs) of AVM and MET were determined against a set of 35 MRSA clinical isolates by broth microdilution assay in cation-adjusted Mueller–Hinton broth following Clinical and Laboratory Standards Institute (CLSI) guideline M07-A8. The type strain S. aureus ATCC 6538 was also included as a meticillin-sensitive S. aureus (MSSA) control. The susceptibility results of 35 MRSA isolates and 1 MSSA to AVM and MET alone and in combination are summarised in Table 1. Consistent with the hospital records, all of the MRSA isolates were resistant to MET (MICs > 100 mg/L) and the MSSA strain was sensitive to MET (MIC = 0.78 mg/L). The MSSA strain and 14 of the 35 clinical MRSA isolates showed moderate susceptibility to AVM alone, with MICs ranging from 6.25 mg/L to 50 mg/L, whilst the others were inherently resistant to AVM (MICs > 100 mg/L). To identify the combination effect of AVM and MET, fractional inhibitory concentration indexes (FICIs) were estimated by the checkerboard assay. Of the 35 clinical MRSA isolates, 30 were
susceptible to the combination with FICIs < 0.5, with 5 others susceptible only to AVM (Table 1). Moreover, it was noteworthy that 21 of these 30 synergy-positive MRSA isolates were resistant to both AVM and MET when treated alone, suggesting a strong synergistic effect. Interestingly, it appeared that AVM could only restore the MET susceptibility in the MRSA isolates, whilst not improving MET efficacy towards the MSSA strain. This phenomenon indicated that the synergism was achieved by re-sensitising MRSA, possibly through interfering with the underlying MET resistance mechanisms that exist only in MRSA. To determine the antimicrobial actions of AVM alone and its combination with MET, four randomly selected MRSA isolates together with the MSSA strain were tested for their survival kinetics following drug treatment (Supplementary Fig. S1). In the AVMtreated group, replication both of MSSA and MRSA isolates was only suppressed by AVM even at 8× MIC, suggesting that AVM alone was bacteriostatic (Supplementary Fig. S1A). In the combination treated group, isolates 19878 and 19976 were steadily killed over time, with ca. 2 log10 decrease in CFU/mL within 12 h, exhibiting a potent bactericidal action (Supplementary Fig. S1B). The combination effects of AVM with other antimicrobials on MRSA were also tested and no synergism or antagonism was detected (data not shown). To our knowledge, this is the first report describing the antistaphylococcal activity of AVM and its bactericidal synergy with MET especially against MRSA. The effect was so pronounced that clinical isolates of MRSA regained sensitivity to MET, which they were previously able to beat, enabling use again of this wellestablished antibiotic against this resistant pathogen. Considering the well-established safety profiles of AVM, we suggest that it could be repurposed as a MET sensitiser for MRSA treatment. The mechanism of MET resistance in MRSA involves the acquisition of foreign genetic elements encoding penicillin-binding protein 2a (PBP2a), which is refractory to inhibition by current -lactam antibiotics while retaining glycosyltransferase and transpeptidase activities [5]. Since the synergistic effect could only be observed among MRSA isolates, it would be worth investigating whether AVM reverses the MET resistance by acting on PBP2a or its transcriptional regulation. This work also proved that ‘drug repurposing’ and ‘drug combination’ could be efficient ways to develop new antibiotics and to overcome drug resistance. Future study is underway to investigate the mechanism of synergy between AVM and MET and to test for their therapeutic efficacy in animal models. Funding: This work was supported in part by grants from the National Natural Science Foundation of China [812111049, 31320103911 and 31125002] and the Ministry of Science and Technology of the People’s Republic of China [2011ZX11102-011-11]. LZ is an awardee for the National Distinguished Young Scholar Program in China.
0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Letters to the Editor / International Journal of Antimicrobial Agents 44 (2014) 274–279
275
Table 1 In vitro inhibitory activity of avermectin (AVM) and its combination with meticillin (MET) against MET-resistant Staphylococcus aureus (MRSA) and MET-sensitive S. aureus (MSSA). Isolate
MRSA isolates 18466 18475 18534 18558 18567 18625 18786 18878 18908 19046 19048 19102 19156 19161 19177 19423 19491 19494 19498 19554 19613 19655 19806 19877 19878 19900 19916 19952 19976 MRSA-A 306-642 306-8-24 309-6 309-7 309-8 ATCC 6538d
Sourcea
CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY CY 306 306 309 309 309 ATCC
In vitro MIC (mg/L) AVM
MET
VAN
AVM + MET combination
12.5 >100 >100 25 25 25 25 >100 25 >100 >100 >100 >100 >100 25 >100 >100 >100 >100 >100 25 >100 >100 >100 25 >100 25 >100 >100 >100 >100 25 6.25 50 50 25
>100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 >100 0.78
0.5 1 1 0.5 0.5 0.5 1 1 0.5 1 1 1 1 1 0.5 1 1 1 1 1 1 1 1 1 0.5 1 1 0.5 1 1 1 0.5 0.5 1 1 1
12.5/–c 25/25 25/12.5 6.25/25 6.25/12.5 25/– 6.25/25 25/0.39 25/– 25/1.56 25/6.25 12.5/12.5 25/1.56 25/12.5 6.25/25 25/6.25 12.5/1.56 12.5/6.25 25/3.125 25/6.25 6.25/25 25/0.78 25/12.5 25/3.125 6.25/25 25/6.25 25/– 12.5/3.125 12.5/3.125 12.5/12.5 12.5/25 6.25/25 6.25/– 12.5/6.25 12.5/6.25 25/– or –/0.78
FICI
Synergyb
>1 <0.5 <0.38 <0.5 <0.38 >1 <0.5 <0.25 >1 <0.27 <0.31 <0.25 <0.27 <0.38 <0.5 <0.31 <0.14 <0.19 <0.28 <0.31 <0.5 <0.26 <0.38 <0.28 <0.5 <0.31 >1 <0.16 <0.16 <0.25 <0.38 <0.5 >1 <0.31 <0.31 >1
N Y Y Y Y N Y Y N Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N Y Y Y Y Y N Y Y N
MIC, minimum inhibitory concentration; VAN, vancomycin; FICI, fractional inhibitory concentration index. a CY, Beijing Chao-Yang Hospital (Beijing, China); 306, The 306th Hospital of People’s Liberation Army (Beijing, China); 309, The 309th Hospital of People’s Liberation Army (Beijing, China). b N, non-synergistic activity; Y, synergistic activity. c –, no contribution to the activity of the combination. d MSSA type strain.
Competing interests: None declared. Ethical approval: Not required. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijantimicag. 2014.05.002. References [1] Barber M. Methicillin-resistant staphylococci. J Clin Pathol 1961;14:385–93. [2] Chong CR, Sullivan Jr DJ. New uses for old drugs. Nature 2007;448:645–6. [3] Campbell WC. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol 2012;13:853–65. [4] Lim LE, Vilchèze C, Ng C, Jacobs Jr WR, Ramón-García S, Thompson CJ. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob Agents Chemother 2013;57: 1040–6. [5] Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog 2002;85:57–72.
Hui Guo a,b,1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China b University of Chinese Academy of Sciences, Beijing 100049, PR China a
Biao Ren 1 Huanqin Dai ∗∗ Shengwang Dai 2 Yuhan Zhang 3 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China Yingmei Liu Bin Cao Beijing Chao-Yang Hospital, Beijing 100020, PR China Lixin Zhang ∗ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, PR China
276
Letters to the Editor / International Journal of Antimicrobial Agents 44 (2014) 274–279 ∗∗ Corresponding
author.
∗ Corresponding author. Present address: Room F816, IMCAS, 1st Beichen West Road, Chaoyang District, Beijing 100101, PR China. Tel.: +86 10 6480 7665; fax: +86 10 6480 7665. E-mail addresses: [email protected] (H. Dai), [email protected] (L. Zhang). 1 2
These two authors contributed equally to this work.
Present address: Beihang University, Beijing 100191, PR China. 3
Present address: Georgetown University Medical Center, Washington, DC 20057, USA. 6 May 2014
http://dx.doi.org/10.1016/j.ijantimicag.2014.05.002
In vitro antimicrobial oxazolidinone tedizolid against Staphylococcus resistant Gram-positive tre study in China
activity of the novel and comparator agents aureus and linezolidpathogens: a multicen-
Sir, Tedizolid, a novel oxazolidinone, acts by inhibiting protein synthesis and has broad activity against Gram-positive pathogens, including strains that are resistant to linezolid [1]. Our previous study indicated that linezolid-resistant coagulase-negative staphylococci (CoNS) and enterococci have emerged in several cities across China, causing serious concern for clinicians. Although several studies have addressed the antibacterial activity of tedizolid against Gram-positive bacteria, this study is the first to provide a specific overview of tedizolid activity in China based on a multicentre study. In total, 100 non-duplicate meticillin-resistant Staphylococcus aureus (MRSA), 100 meticillin-sensitive S. aureus (MSSA), 43 linezolid-resistant CoNS and 17 linezolid-resistant enterococci isolates were collected from 16 teaching hospitals across China from 2009 to 2013. One-half of the S. aureus isolates were recovered from skin and soft-tissue infections and the other half
were recovered from lower respiratory tract infections. Of the 43 linezolid-resistant CoNS isolates, 42 (97.7%) were recovered from bacteraemia and 1 (2.3%) was recovered from a urinary tract infection (UTI). Among the 17 linezolid-resistant enterococci, 7 isolates (41.2%) were recovered from wound infections, 7 (41.2%) were recovered from UTIs and 3 (17.6%) were recovered from bacteraemia. Minimum inhibitory concentration (MIC) data for each antibiotic were determined using the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Of the 200 S. aureus strains, including 100 MRSA and 100 MSSA, tedizolid, vancomycin, daptomycin, tigecycline and linezolid were the most active agents (100% effective). For the 100 MRSA isolates, the MIC50 and MIC90 values (MIC required to inhibit 50% and 90% of the isolates, respectively) for tedizolid were both 0.25 mg/L, whilst these two values were 2 mg/L for linezolid (Table 1). For the 100 MSSA isolates, the MIC50 and MIC90 values for tedizolid were 0.25 mg/L and 0.5 mg/L, respectively, whilst both values were 2 mg/L for linezolid. The distribution peaks for tedizolid and linezolid MICs were 0.25 mg/L and 2 mg/L, respectively, indicating that the potency of tedizolid against S. aureus was eightfold greater than it was for linezolid. The tedizolid MICs of 99% of the S. aureus strains were ≤0.5 mg/L. In another study, tedizolid exhibited 4- to 16fold greater activity than linezolid against Gram-positive species, including MRSA [2]. All CoNS included in this study were resistant to meticillin and linezolid, and all were multiresistant. Vancomycin, daptomycin and tigecycline were the most active agents against all of the isolates (100% effective). For the 43 linezolid-resistant CoNS isolates, the MIC50 and MIC90 values for tedizolid were 2 mg/L and 4 mg/L, respectively, whilst these values were 256 mg/L and >256 mg/L, respectively, for linezolid (Table 1). Both the MIC50 and MIC90 for tedizolid against CoNS were ≥64-fold lower than for linezolid. Of the 43 linezolid-resistant CoNS isolates, 38 (88.4%) harboured the multidrug resistance gene cfr and 31 (72.1%) had the G2576T mutation in the 23S rRNA gene; 26 (60.5%) had both the cfr gene and the G2576T mutation. CoNS with cfr and/or the G2576T mutation in the 23S rRNA gene had a high MIC (8 mg/L to >256 mg/L) for linezolid, whilst tedizolid retained high antimicrobial activity
Table 1 Antimicrobial activities of tedizolid and linezolid against Staphylococcus aureus, coagulase-negative staphylococci (CoNS) and enterococci isolates. Antimicrobial agent/phenotype
N
MIC (mg/L) MIC50
Tedizolid All S. aureus MSSA MRSA All linezolid-resistant CoNS CoNS with cfr gene and G2576T mutation CoNS with only cfr gene CoNS with only G2576T mutation Linezolid-resistant enterococci Linezolid All S. aureus MSSA MRSA All linezolid-resistant CoNS CoNS with cfr gene and G2576T mutation CoNS with only cfr gene CoNS with only G2576T mutation Linezolid-resistant enterococci
200 100 100 43 26 12 5 17 200 100 100 43 26 12 5 17
0.25 0.25 0.25 2 2 2 2 0.5 2 2 2 256 256 >256 16 8
MIC90 0.5 0.5 0.25 4 4 4 2 1 2 2 2 >256 >256 >256 256 16
Range 0.064–1 0.125–1 0.064–1 0.12–4 0.5–4 0.12–4 1–2 0.5–2 0.25–4 1–2 0.25–4 8 to >256 8 to >256 8 to >256 8–256 8–16
MIC, minimum inhibitory concentration; MIC50/90 , MIC required to inhibit 50% and 90% of the isolates, respectively; MSSA, meticillin-sensitive S. aureus; MRSA, meticillinresistant S. aureus.