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Spread of Klebsiella pneumoniae carbapenemase-2-producing Klebsiella pneumoniae clones in Asia “...combination therapy comprising at least two antimicrobial agents has been shown to reduce the mortality rate among patients with Klebsiella pneumoniae carbapenemaseproducing Klebsiella pneumoniae.” Shio-Shin Jean1 & Po-Ren Hsueh*,2
Infections caused by carbapenem-resistant Enterobacteriaceae spp., especially those that produce Klebsiella pneumoniae carbapenemase (KPC), are associated with a high in-hospital mortality rate (ranging from 39 to 45%) [1–4] . In Taiwan, carbapenem resistance among Enterobacteriaceae spp. increased markedly from 2003 to 2012. During the latter part of 2012, the rate of nonsusceptibility to carbapenems among nosocomial isolates collected from patients in intensive care units was 10% for enteric Gram-negative bacteria (GNB), 4% for Escherichia coli and 16% for K. pneumoniae [5] . Most clinical laboratories are not equipped with the means to detect carbapenemase production in isolates of Enterobacteriaceae. The modified Hodge test (MHT), dipicolinic acid-based inhibition testing and laboratory methods that test for inhibition of boronic acid can detect the existence of class A and class B carbapenemases in Enterobacteriaceae. However, these methods are time-consuming to perform and have questionable sensitivity and specificity in terms of detecting various kinds of carbapenemases [1–2,4] .
During the period of 2006–2009, approximately two-thirds of all KPC-2producing K. pneumoniae isolates in hospitals in Zhejiang, Jiangsu and Anhui (located in southeastern China, the epicenter of ST 11 clone, blaKPC-2 K. pneumoniae) were sequence type 11 clones. No sequence type 258 clones (a single-locus variant of ST 11) were found in that region [6] . By contrast, Ma et al. found that blaIMP-8 was the sole carbapenemase in 29 imipenem-nonsusceptible (NS; mostly MIC >2 mg/l) K. pneumoniae isolates collected in Taiwan during the period 2002–2009 [7] . Hung et al. found that no MHT-positive Enterobacteriaceae spp. carried the blaKPC gene before 2011 [8] . Since then, sequence type 11 has been the predominant K. pneumoniae clone, displaying high potential for simultaneously acquiring multiple resistance mechanisms (comprising blaCTX-M, blaDHA, blaCMY and mutated genes conferring decreased expression of OmpK35/36 porin) [7] . The first clinically proven KPCproducing K. pneumoniae bacteremic isolate in Taiwan was identified in 2010 in a patient who had just returned from the
KEYWORDS
• amikacin • carbapenem • China • colistin • combination therapy • Klebsiella pneumoniae carbapenemase • sequence type 11 • Taiwan • tigecycline
Department of Emergency Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan *Author for correspondence: [email protected] 1 2
10.2217/FMB.13.157 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(3), 273–275
part of
ISSN 1746-0913
273
Editorial Jean & Hsueh
“Most clinical laboratories are not equipped with the means to detect carbapenemase production in isolates of Enterobacteriaceae.”
274
Chinese province of Zhejiang [9] . Shortly thereafter, two Taiwanese patients who were hospitalized in the same ward with the aforementioned patient developed infections (urinary tract infection [UTI] and pneumonia, respectively) caused by KPC-2-producing, sequence type 11 K. pneumoniae. In 2011, a nationwide survey of the prevalence of carbapenemase (class A, class B)-producing Enterobacteriaceae carriers revealed that 5.2% of ertapenem-nonsusceptible (MIC >0.5mg/l) Enterobacteriaceae isolates (all were K. pneumoniae) harbored genes encoding KPC-2 carbapenemase [10] . A similar survey in 2011 was conducted by Chiu et al. [11] , who showed that the prevalence rate of resistance to imipenem or meropenem (MIC >1.0mg/l) among isolates harboring various carbapenemase genes (primarily blaKPC-2) was significantly higher in 2012 than in 2010 (16.6 vs 0% for prevalence of KPC-2 carriers among K. pneumonia; p < 0.0001). In addition, typing analysis of all KPC-2-producing isolates revealed that the K. pneumoniae strain with sequence type 11 was also the main KPC clone in Taiwan from 2011 through to 2012. These facts strongly suggest that occult inter-hospital dissemination of KPC-K. pneumoniae in Taiwan probably emerged in 2011. Studies in Asia have shown that these isolates were not the same as those isolated in China [12] . To the best of our knowledge, K. pneumoniae clones with sequence type 11 harboring the blaKPC-2 gene have not been reported in Japan [13] , South Korea [14] , the Arabian Peninsula [15] , Thailand, Myanmar, Vietnam or the Indian subcontinent. The results of in vitro conjugation experiments in E. coli demonstrated that blaKPC-2 could be transferred with the assistance of flanking insertion sequence 26 (in the form of composite transposon) and the transfer operon (locus tra-trb) [16] . Further investigations of cross-species transmission of the blaKPC-2 gene are warranted. In comparison to β-lactam agents, a high rate (100%) of in vitro susceptibility to amikacin (MIC range: 0.5–2 mg/l) was demonstrated against KPC-2-producing K. pneumoniae isolates collected in 2011 in Taiwan [10] . The high amikacin susceptibility rate is not found among blaKPC-2-carrying K. pneumoniae isolates in China [6] . According to the criteria proposed by the US FDA (susceptibility for tigecycline being defined as 16 mg/l. Consequently, monotherapy with either of the above agents (tigecycline, colistin and carbapenems) should not be expected to achieve reliably effective treatment results. By contrast, combination therapy comprising at least two antimicrobial agents has been shown to reduce the mortality rate among patients with KPC-producing K. pneumoniae. The recommended regimens include one carbapenem drug plus tigecyline or colistin [2] , colistin plus one aminoglycoside agent (treating those with a UTI) [21] , tigecycline combined with colistin, and meropenem (a good protective factor from mortality in univariate analysis, with an odds ratio of 0.27 [95% CI: 0.07–1.01; p = 0.009]) [3] . In addition, tigecycline plus colistin has been shown to be the most effective regimen against KPC producers [21] .
future science group
Spread of K. pneumoniae carbapenemase-2-producing K. pneumoniae clones in Asia Financial & competing interests disclosure The authors have no other relevant affiliations, or financial involvement with any organization, or entity with a financial interest in, or financial conflict with the subject matter
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Liu SW, Chang HJ, Chia JH, Kuo AJ, Wu TL, Lee MH. Outcomes and characteristics of ertapenem-nonsusceptible Klebsiella pneumoniae bacteremia at a university hospital in Northern Taiwan: a matched case–control study. J. Microbiol. Immunol. Infect. 45(2), 113–119 (2012). Qureshi ZA, Paterson DL, Potoski BA et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob. Agents. Chemother. 56(4), 2108–2113 (2012). Tumbarello M, Viale P, Viscoli C et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumonia carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin. Infect. Dis. 55(7), 943–950 (2012). Jean SS, Lee WS, Hsueh PR. Nationwide spread of Klebsiella pneumoniae carbapenemase-2-producing K. pneumoniae sequence type 11 in Taiwan. J. Microbiol. Immunol. Infect. 46(5), 317–319 (2013). Centers for Disease Control and Prevention of Taiwan. The monitor report, from Taiwanese Nosocomial Infection Surveillance System, in the third quarter of 2012 (written in Chinese). www.taichung.gov.tw/public/ Data/31411292471.pdf Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J. Antimicrob. Chemother. 66(2), 307–312 (2011). Ma L, Lu PL, Siu LK, Hsieh MH. Molecular typing and resistance mechanisms of imipenem-non-susceptible Klebsiella
future science group
or materials discussed in manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony. No writing assistance was utilized in the production of this manuscript. pneumoniae in Taiwan: results from the Taiwan surveillance of antibiotic resistance (TSAR) study, 2002–2009. J. Med. Microbiol. 62(1), 101–107 (2013).
References
8
9
Editorial
Hung KH, Yan JJ, Lu JJ, Chen HM, Wu JJ. Characterization of the modified Hodge test-positive isolates of Enterobacteriaceae in Taiwan. J. Microbiol. Immunol. Infect. 46(1), 35–40 (2013). Chung KP, Tseng SP, Huang YT, Tsai TH, Teng LJ, Hsueh PR. Arrival of Klebsiella pneumoniae carbapenemase (KPC)-2 in Taiwan. J. Antimicrob. Chemother. 66(5), 1182–1184 (2011).
10 Lee CM, Liao CH, Lee WS et al. Outbreak
of Klebsiella pneumonia carbapenemase-2producing K. pneumonia sequence type 11 in Taiwan in 2011. Antimicrob. Agents. Chemother. 56(10), 5016–5022 (2012). 11 Chiu SK, Wu TL, Chuang YC et al. National
surveillance study on carbapenem nonsusceptible Klebsiella pneumoniae in Taiwan: the emergence and rapid dissemination of KPC-2 carbapenemase. PLoS ONE 8(7), e69428–e69434 (2013). 12 Balm MN, Ngan G, Jureen R, Lin RT, Teo J.
Molecular characterization of newly emerged bla KPC-2-producing Klebsiella pneumoniae in Singapore. J. Clin. Microbiol. 50(2), 475–476 (2012). 13 Koyano S, Saito R, Nagai R et al. Molecular
characterization of carbapenemase-producing clinical isolates of Enterobacteriaceae in a teaching hospital, Japan. J. Med. Microbiol. 62(3), 446–450 (2013). 14 Yoo JS, Kim HM, Yoo JI et al. Detection of
clonal KPC-2-producing Klebsiella pneumonia ST258 in Korea during nationwide surveillance in 2011. J. Med. Microbiol. 62(9), 1338–1342 (2013).
15 Zowawi HM, Balkhy HH, Walsh TR,
Paterson DL. β-lactamase production in key Gram-negative pathogen isolates from the Arabian Peninsula. Clin. Microbiol. Rev. 26(3), 361–380 (2013). 16 Chen YT, Lin JC, Fung CP et al. KPC-2-
encoding plasmids from Escherichia coli and Klebsiella pneumoniae in Taiwan. J. Antimicrob. Chemother. doi:10.1093/jac/ dkt409 (2013) (Epub ahead of print). 17 Huang SR, Liu MF, Lin CF, Shi ZY.
Molecular surveillance and clinical outcomes of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae infections. J. Microbiol. Immunol. Infect. doi:10.1016/j.jmii.08.029 (2012) (Epub ahead of print). 18 Spanu T, De Angelis G, Cipriani M et al.
In vivo emergence of tigecycline resistance in multidrug-resistant Klebsiella pneumoniae and Escherichia coli. Antimicrob. Agents. Chemother. 56(8), 4516–4518 (2012). 19 Lee J, Patel G, Huprikar S, Calfee DP,
Jenkins SG. Decreased susceptibility to polymyxin B during treatment for carbapenem-resistant Klebsiella pneumoniae infection. J. Clin. Microbiol. 47(5), 1611–1612 (2009). 20 Kuti JL, Dandekar PK, Nightingale CH,
Nicolau DP. Use of Monte Carlo simulation to design an optimized pharmacodynamics dosing strategy for meropenem. J. Clin. Pharmacol. 43(10), 1116–1123 (2003). 21 Lee GC, Burgess DS. Treatment of Klebsiella
pneumoniae carbapenemase (KPC) infections: a review of published case series and case reports. Ann. Clin. Microbiol. Antimicrob. 11, 32–40 (2012).
www.futuremedicine.com
275
Spread of Klebsiella pneumoniae carbapenemase-2-producing Klebsiella pneumoniae clones in Asia “...combination therapy comprising at least two antimicrobial agents has been shown to reduce the mortality rate among patients with Klebsiella pneumoniae carbapenemaseproducing Klebsiella pneumoniae.” Shio-Shin Jean1 & Po-Ren Hsueh*,2
Infections caused by carbapenem-resistant Enterobacteriaceae spp., especially those that produce Klebsiella pneumoniae carbapenemase (KPC), are associated with a high in-hospital mortality rate (ranging from 39 to 45%) [1–4] . In Taiwan, carbapenem resistance among Enterobacteriaceae spp. increased markedly from 2003 to 2012. During the latter part of 2012, the rate of nonsusceptibility to carbapenems among nosocomial isolates collected from patients in intensive care units was 10% for enteric Gram-negative bacteria (GNB), 4% for Escherichia coli and 16% for K. pneumoniae [5] . Most clinical laboratories are not equipped with the means to detect carbapenemase production in isolates of Enterobacteriaceae. The modified Hodge test (MHT), dipicolinic acid-based inhibition testing and laboratory methods that test for inhibition of boronic acid can detect the existence of class A and class B carbapenemases in Enterobacteriaceae. However, these methods are time-consuming to perform and have questionable sensitivity and specificity in terms of detecting various kinds of carbapenemases [1–2,4] .
During the period of 2006–2009, approximately two-thirds of all KPC-2producing K. pneumoniae isolates in hospitals in Zhejiang, Jiangsu and Anhui (located in southeastern China, the epicenter of ST 11 clone, blaKPC-2 K. pneumoniae) were sequence type 11 clones. No sequence type 258 clones (a single-locus variant of ST 11) were found in that region [6] . By contrast, Ma et al. found that blaIMP-8 was the sole carbapenemase in 29 imipenem-nonsusceptible (NS; mostly MIC >2 mg/l) K. pneumoniae isolates collected in Taiwan during the period 2002–2009 [7] . Hung et al. found that no MHT-positive Enterobacteriaceae spp. carried the blaKPC gene before 2011 [8] . Since then, sequence type 11 has been the predominant K. pneumoniae clone, displaying high potential for simultaneously acquiring multiple resistance mechanisms (comprising blaCTX-M, blaDHA, blaCMY and mutated genes conferring decreased expression of OmpK35/36 porin) [7] . The first clinically proven KPCproducing K. pneumoniae bacteremic isolate in Taiwan was identified in 2010 in a patient who had just returned from the
KEYWORDS
• amikacin • carbapenem • China • colistin • combination therapy • Klebsiella pneumoniae carbapenemase • sequence type 11 • Taiwan • tigecycline
Department of Emergency Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan *Author for correspondence: [email protected] 1 2
10.2217/FMB.13.157 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(3), 273–275
part of
ISSN 1746-0913
273
Editorial Jean & Hsueh
“Most clinical laboratories are not equipped with the means to detect carbapenemase production in isolates of Enterobacteriaceae.”
274
Chinese province of Zhejiang [9] . Shortly thereafter, two Taiwanese patients who were hospitalized in the same ward with the aforementioned patient developed infections (urinary tract infection [UTI] and pneumonia, respectively) caused by KPC-2-producing, sequence type 11 K. pneumoniae. In 2011, a nationwide survey of the prevalence of carbapenemase (class A, class B)-producing Enterobacteriaceae carriers revealed that 5.2% of ertapenem-nonsusceptible (MIC >0.5mg/l) Enterobacteriaceae isolates (all were K. pneumoniae) harbored genes encoding KPC-2 carbapenemase [10] . A similar survey in 2011 was conducted by Chiu et al. [11] , who showed that the prevalence rate of resistance to imipenem or meropenem (MIC >1.0mg/l) among isolates harboring various carbapenemase genes (primarily blaKPC-2) was significantly higher in 2012 than in 2010 (16.6 vs 0% for prevalence of KPC-2 carriers among K. pneumonia; p < 0.0001). In addition, typing analysis of all KPC-2-producing isolates revealed that the K. pneumoniae strain with sequence type 11 was also the main KPC clone in Taiwan from 2011 through to 2012. These facts strongly suggest that occult inter-hospital dissemination of KPC-K. pneumoniae in Taiwan probably emerged in 2011. Studies in Asia have shown that these isolates were not the same as those isolated in China [12] . To the best of our knowledge, K. pneumoniae clones with sequence type 11 harboring the blaKPC-2 gene have not been reported in Japan [13] , South Korea [14] , the Arabian Peninsula [15] , Thailand, Myanmar, Vietnam or the Indian subcontinent. The results of in vitro conjugation experiments in E. coli demonstrated that blaKPC-2 could be transferred with the assistance of flanking insertion sequence 26 (in the form of composite transposon) and the transfer operon (locus tra-trb) [16] . Further investigations of cross-species transmission of the blaKPC-2 gene are warranted. In comparison to β-lactam agents, a high rate (100%) of in vitro susceptibility to amikacin (MIC range: 0.5–2 mg/l) was demonstrated against KPC-2-producing K. pneumoniae isolates collected in 2011 in Taiwan [10] . The high amikacin susceptibility rate is not found among blaKPC-2-carrying K. pneumoniae isolates in China [6] . According to the criteria proposed by the US FDA (susceptibility for tigecycline being defined as 16 mg/l. Consequently, monotherapy with either of the above agents (tigecycline, colistin and carbapenems) should not be expected to achieve reliably effective treatment results. By contrast, combination therapy comprising at least two antimicrobial agents has been shown to reduce the mortality rate among patients with KPC-producing K. pneumoniae. The recommended regimens include one carbapenem drug plus tigecyline or colistin [2] , colistin plus one aminoglycoside agent (treating those with a UTI) [21] , tigecycline combined with colistin, and meropenem (a good protective factor from mortality in univariate analysis, with an odds ratio of 0.27 [95% CI: 0.07–1.01; p = 0.009]) [3] . In addition, tigecycline plus colistin has been shown to be the most effective regimen against KPC producers [21] .
future science group
Spread of K. pneumoniae carbapenemase-2-producing K. pneumoniae clones in Asia Financial & competing interests disclosure The authors have no other relevant affiliations, or financial involvement with any organization, or entity with a financial interest in, or financial conflict with the subject matter
1
2
3
4
5
6
7
Liu SW, Chang HJ, Chia JH, Kuo AJ, Wu TL, Lee MH. Outcomes and characteristics of ertapenem-nonsusceptible Klebsiella pneumoniae bacteremia at a university hospital in Northern Taiwan: a matched case–control study. J. Microbiol. Immunol. Infect. 45(2), 113–119 (2012). Qureshi ZA, Paterson DL, Potoski BA et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob. Agents. Chemother. 56(4), 2108–2113 (2012). Tumbarello M, Viale P, Viscoli C et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumonia carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin. Infect. Dis. 55(7), 943–950 (2012). Jean SS, Lee WS, Hsueh PR. Nationwide spread of Klebsiella pneumoniae carbapenemase-2-producing K. pneumoniae sequence type 11 in Taiwan. J. Microbiol. Immunol. Infect. 46(5), 317–319 (2013). Centers for Disease Control and Prevention of Taiwan. The monitor report, from Taiwanese Nosocomial Infection Surveillance System, in the third quarter of 2012 (written in Chinese). www.taichung.gov.tw/public/ Data/31411292471.pdf Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J. Antimicrob. Chemother. 66(2), 307–312 (2011). Ma L, Lu PL, Siu LK, Hsieh MH. Molecular typing and resistance mechanisms of imipenem-non-susceptible Klebsiella
future science group
or materials discussed in manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony. No writing assistance was utilized in the production of this manuscript. pneumoniae in Taiwan: results from the Taiwan surveillance of antibiotic resistance (TSAR) study, 2002–2009. J. Med. Microbiol. 62(1), 101–107 (2013).
References
8
9
Editorial
Hung KH, Yan JJ, Lu JJ, Chen HM, Wu JJ. Characterization of the modified Hodge test-positive isolates of Enterobacteriaceae in Taiwan. J. Microbiol. Immunol. Infect. 46(1), 35–40 (2013). Chung KP, Tseng SP, Huang YT, Tsai TH, Teng LJ, Hsueh PR. Arrival of Klebsiella pneumoniae carbapenemase (KPC)-2 in Taiwan. J. Antimicrob. Chemother. 66(5), 1182–1184 (2011).
10 Lee CM, Liao CH, Lee WS et al. Outbreak
of Klebsiella pneumonia carbapenemase-2producing K. pneumonia sequence type 11 in Taiwan in 2011. Antimicrob. Agents. Chemother. 56(10), 5016–5022 (2012). 11 Chiu SK, Wu TL, Chuang YC et al. National
surveillance study on carbapenem nonsusceptible Klebsiella pneumoniae in Taiwan: the emergence and rapid dissemination of KPC-2 carbapenemase. PLoS ONE 8(7), e69428–e69434 (2013). 12 Balm MN, Ngan G, Jureen R, Lin RT, Teo J.
Molecular characterization of newly emerged bla KPC-2-producing Klebsiella pneumoniae in Singapore. J. Clin. Microbiol. 50(2), 475–476 (2012). 13 Koyano S, Saito R, Nagai R et al. Molecular
characterization of carbapenemase-producing clinical isolates of Enterobacteriaceae in a teaching hospital, Japan. J. Med. Microbiol. 62(3), 446–450 (2013). 14 Yoo JS, Kim HM, Yoo JI et al. Detection of
clonal KPC-2-producing Klebsiella pneumonia ST258 in Korea during nationwide surveillance in 2011. J. Med. Microbiol. 62(9), 1338–1342 (2013).
15 Zowawi HM, Balkhy HH, Walsh TR,
Paterson DL. β-lactamase production in key Gram-negative pathogen isolates from the Arabian Peninsula. Clin. Microbiol. Rev. 26(3), 361–380 (2013). 16 Chen YT, Lin JC, Fung CP et al. KPC-2-
encoding plasmids from Escherichia coli and Klebsiella pneumoniae in Taiwan. J. Antimicrob. Chemother. doi:10.1093/jac/ dkt409 (2013) (Epub ahead of print). 17 Huang SR, Liu MF, Lin CF, Shi ZY.
Molecular surveillance and clinical outcomes of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae infections. J. Microbiol. Immunol. Infect. doi:10.1016/j.jmii.08.029 (2012) (Epub ahead of print). 18 Spanu T, De Angelis G, Cipriani M et al.
In vivo emergence of tigecycline resistance in multidrug-resistant Klebsiella pneumoniae and Escherichia coli. Antimicrob. Agents. Chemother. 56(8), 4516–4518 (2012). 19 Lee J, Patel G, Huprikar S, Calfee DP,
Jenkins SG. Decreased susceptibility to polymyxin B during treatment for carbapenem-resistant Klebsiella pneumoniae infection. J. Clin. Microbiol. 47(5), 1611–1612 (2009). 20 Kuti JL, Dandekar PK, Nightingale CH,
Nicolau DP. Use of Monte Carlo simulation to design an optimized pharmacodynamics dosing strategy for meropenem. J. Clin. Pharmacol. 43(10), 1116–1123 (2003). 21 Lee GC, Burgess DS. Treatment of Klebsiella
pneumoniae carbapenemase (KPC) infections: a review of published case series and case reports. Ann. Clin. Microbiol. Antimicrob. 11, 32–40 (2012).
www.futuremedicine.com
275
