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In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART)
G Model
JGAR-87; No. of Pages 2 Journal of Global Antimicrobial Resistance xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Global Antimicrobial Resistance journal homepage: www.elsevier.com/locate/jgar
Letter to the Editor In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) Sir, Nosocomial infections cause significant morbidity and mortality, further compounded by increasing rates of bacterial resistance among common pathogens and a relative dearth of new antibiotic options, ensuing lengthy hospital stays, increasing use of antibiotics, increasing healthcare costs, and spreading of resistance into the community. Urinary tract infections (UTIs) represent one of the most frequently encountered infections in health care. Surveillance may help to identify antimicrobial susceptibility trends and provide data for the timely adaptation of empirical treatment guidelines. Starting in late 2009, the Study for Monitoring Antimicrobial Resistance Trends (SMART) has monitored the in vitro susceptibility profiles of Gram-negative bacilli causing UTIs and intra-abdominal infections. SMART has documented the high prevalence of antibiotic resistance in Asia [1]. This report summarises the susceptibility to commonly used antimicrobials among isolates causing UTIs in four tertiary care centres in Vietnam. Two hospitals in Ho Chi Minh City and two hospitals in Hanoi collected non-duplicate Gram-negative isolates during the period 2010–2011 from patients with UTI. A total of 341 UTI isolates were collected. Enterobacteriaceae accounted for the majority of the isolates (293/341; 85.9%). Escherichia coli (225/293; 76.8%) and Klebsiella pneumoniae (27/293; 9.2%) accounted for 86.0% of all Enterobacteriaceae. Identification and antimicrobial susceptibility testing using broth microdilution were performed at a central laboratory according to Clinical and Laboratory Standards Institute (CLSI) guidelines [2]. Susceptibility was categorised and quality control was performed following CLSI guidelines [3].
Extended-spectrum b-lactamase (ESBL) phenotypes among E. coli, K. pneumoniae, Klebsiella oxytoca and Proteus mirabilis isolates were determined according to CLSI guidelines [3]. Isolates were categorised as community-associated (CA) if collected <48 h after hospitalisation and as hospital-associated (HA) if collected 48 h after hospitalisation. Rates of susceptibility to 12 antimicrobial agents are presented in Table 1. For E. coli and K. pneumoniae, the most effective antibiotic in vitro was ertapenem, followed by amikacin, imipenem and piperacillin/tazobactam (TZP). Low susceptibility rates to most antimicrobials were observed for Pseudomonas aeruginosa (range 40–60%) and Acinetobacter baumannii (range 29–57%). Only ertapenem (92.5%) and imipenem (88.8%) had percent susceptible values that were acceptable against K. pneumoniae. In contrast, E. coli and K. pneumoniae, which accounted for 73.9% of the UTI pathogens in this study, displayed high rates of resistance to fluoroquinolones (ciprofloxacin and levofloxacin) and third- and fourth-generation cephalosporins, even higher than was reported recently from the Asia-Pacific region [4]. Pseudomonas aeruginosa and A. baumannii had typically higher rates of resistance to all drug classes than Enterobacteriaceae. Since these two species represented >12% of the Gramnegative bacilli in this study, their high resistance rates are quite alarming. Carbapenems are considered the treatment of choice for ESBL-positive organisms and resistance to this class is problematic for patient therapy [4]. Among the isolates with a determined environmental source of infection, 28.7% were CA and 70.0% were HA, and the ranking of species was similar in both patient populations. ESBL production was detected in 62.7% of E. coli and 44.4% of K. pneumoniae. The prevalence of both ESBL-positive Enterobacteriaceae and nonfermenters was higher among patients with HA UTIs compared with CA UTIs. The rate of ESBL-positive E. coli (63.9%) and K. pneumoniae (50.0%) in HA UTI was marginally higher than isolates from CA UTIs for E. coli but not for K. pneumoniae. The most
Table 1 In vitro susceptibilities (%) of Enterobacteriaceae and non-Enterobacteriaceae collected from patients with urinary tract infections in Vietnam during 2010–2011.a Organism (n)
SAM
AMK
CTX
CAZ
CFT
FOX
CIP
CEF
ERT
IPM
LVX
TZP
Enterobacteriaceae Escherichia coli (225) E. coli, ESBL + (141) Klebsiella pneumoniae (27) K. pneumoniae, ESBL + (12)
13.7 9.9 33.3 0.0
96.0 94.3 81.4 58.3
24.8 1.4 40.7 0.0
36.4 19.1 48.1 16.6
24 0.0 40.7 0.0
67.5 70.9 74.0 75.0
20.8 11.3 44.4 8.3
31.1 2.8 44.4 0.0
98.6 99.2 92.5 91.6
99.1 99.2 88.8 91.6
21.7 12.0 48.1 8.3
81.3 82.9 74.0 58.3
Non-fermenters Pseudomonas aeruginosa (30) Acinetobacter spp. (14)
–b 35.7
56.6 35.7
– 28.5
46.6 28.5
– 28.5
– –
40.0 35.7
40.0 28.5
– –
60.0 57.1
40.0 42.8
46.6 50.0
SAM, ampicillin/sulbactam; AMK, amikacin; CTX, ceftriaxone; CAZ, ceftazidime; CFT, cefotaxime; FOX, cefoxitin; CIP, ciprofloxacin: CEF, cefepime; ERT, ertapenem; IPM, imipenem; LVX, levofloxacin; TZP, piperacillin/tazobactam; ESBL, extended-spectrum b-lactamase. a Based on Clinical and Laboratory Standards Institute (CLSI) 2013 breakpoints [3]. b A dash indicates that no breakpoints exist for this species. http://dx.doi.org/10.1016/j.jgar.2014.04.003 2213-7165/ß 2014 Published by Elsevier Ltd on behalf of International Society for Chemotherapy of Infection and Cancer.
Please cite this article in press as: Thi Thanh Nga T, et al. In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J Global Antimicrob Resist (2014), http://dx.doi.org/10.1016/j.jgar.2014.04.003
G Model
JGAR-87; No. of Pages 2 2
Letter to the Editor / Journal of Global Antimicrobial Resistance xxx (2014) xxx–xxx
effective antibiotics against these two ESBL-positive species were ertapenem and imipenem (92–99% susceptible), amikacin (94.3% susceptible, E. coli only) and TZP (82.9% susceptible, E. coli only). Rates of susceptibility to all other agents tested were <75% for both species. Susceptibility to amikacin and TPZ among ESBL-positive K. pneumoniae (both 58.3%) was lower compared with ESBL-positive E. coli. Although these data from Vietnam are somewhat limited, this study is among the first to give a snapshot of the burden of antibiotic resistance among Gram-negative isolates from UTI in this country and highlights increasing resistance among ESBL-producing Enterobacteriaceae in Vietnam and the AsiaPacific region, as has been reported elsewhere [1,4–6]. The current data showed alarmingly high ESBL rates (45%) in Vietnam compared with the Asia/Pacific region average of 28.2%. The study was not designed to demonstrate causality and the two large cities may not accurately represent the entire country. However, in view of excessive antibiotic consumption as reported in a surveillance study from Vietnam [274 defined daily doses (DDD) per 100 bed-days in Vietnam compared with 58 DDD per 100 bed-days in The Netherlands in the same year], and with second- and third-generation cephalosporins and fluoroquinolones used as workhorse antibiotics, the likelihood of disproportionate antibiotic consumption causing selection pressure and antibiotic resistance cannot be disregarded, as illustrated in previous studies [7]. Therefore, utilisation of these agents should be closely monitored to ensure appropriateness of use. In view of the high prevalence of ESBL-producing isolates and a relatively limited selection of antibiotics to treat multiresistant infections, this study emphasises the need for enhanced infection control and antibiotic stewardship programmes. Treatment regimens driven by guidelines, coupled with infection control measures, are needed to reduce the adverse consequences of antimicrobial misuse. Funding This study was funded by Merck & Co., Inc. (protocol number CLI-486). Competing interest DJB and REB served as scientific advisors or consultants to Merck and received research support from Merck to conduct this study; PN and TGP are affiliated with MSD, a subsidiary of Merck & Co., Inc. All other authors declare no competing interests. Ethical approval Not required. Acknowledgments The authors thank all SMART investigators for their participation in this programme.
References [1] Hawser SP, Bouchillon SK, Hoban DJ, Badal RE, Hsueh PR, Paterson DL. Emergence of high levels of extended-spectrum-b-lactamase-producing Gram-negative bacilli in the Asia-Pacific region: data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program, 2007. Antimicrob Agents Chemother 2009;53:3280–4. [2] Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. 9th ed. Wayne, PA: CLSI; 2012, Document M07-A9. [3] Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-third informational supplement. Wayne, PA: CLSI; 2013, Document M100-S23. [4] Lu PL, Liu YC, Toh HS, Lee YL, Liu YM, Ho CM, et al. Epidemiology and antimicrobial susceptibility profiles of Gram-negative bacteria causing urinary tract infections in the Asia-Pacific region: 2009-2010 results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Int J Antimicrob Agents 2012;40(Suppl.):S37–43. [5] Meier S, Weber R, Zbinden R, Ruef C, Hasse B. Extended-spectrum b-lactamaseproducing Gram-negative pathogens in community-acquired urinary tract infections: an increasing challenge for antimicrobial therapy. Infection 2011;39:333–40. [6] Hsu LY, Tan TY, Tam VH, Kwa A, Fisher DA, Koh TH. Network for Antimicrobial Resistance Surveillance (Singapore). Surveillance and correlation of antibiotic prescription and resistance of Gram-negative bacteria in Singaporean hospitals. Antimicrob Agents Chemother 2010;54:1173–8. [7] Global Antibiotic Resistance Partnership. First report on antibiotic use and resistance in Vietnam hospitals in 2008–2009. A report from the Ministry of Health of the Socialist Republic of Vietnam in collaboration with the Global Antibiotic Resistance Partnership and Oxford University Clinical Research Unit, http://benhnhietdoi.vn/data/files/documents/Report_on_antibiotics_use_and_ resistance_in_15_hospitals_in_2008-2009.pdf [accessed 29.04.14].
Tran Thi Thanh Nga Cho Ray Hospital, Ho Chi Minh City, Viet Nam Tran Thi Lan Phuong Viet Duc Hospital, Hanoi, Viet Nam Tran My Phuong Binh Dan Hospital, Ho Chi Minh City, Viet Nam Doan Mai Phuong Bach Mai Hospital, Hanoi, Viet Nam Douglas J. Biedenbach* International Health Management Associates, Inc., Schaumburg, IL, USA Prashant Narang MSD Pharmaceuticals Pvt. Ltd., India Trong Giao Phan MSD Pharmaceuticals Pvt. Ltd., Viet Nam Robert E. Badal International Health Management Associates, Inc., Schaumburg, IL, USA *Corresponding author. Present address: 2122 Palmer Drive, Schaumburg, IL 60173, USA. Tel.: +1 847 303 5003/847 664 9426; fax: +1 847 303 5601 E-mail address: [email protected] (D.J. Biedenbach). 21 October 2013
Please cite this article in press as: Thi Thanh Nga T, et al. In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J Global Antimicrob Resist (2014), http://dx.doi.org/10.1016/j.jgar.2014.04.003
JGAR-87; No. of Pages 2 Journal of Global Antimicrobial Resistance xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Global Antimicrobial Resistance journal homepage: www.elsevier.com/locate/jgar
Letter to the Editor In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) Sir, Nosocomial infections cause significant morbidity and mortality, further compounded by increasing rates of bacterial resistance among common pathogens and a relative dearth of new antibiotic options, ensuing lengthy hospital stays, increasing use of antibiotics, increasing healthcare costs, and spreading of resistance into the community. Urinary tract infections (UTIs) represent one of the most frequently encountered infections in health care. Surveillance may help to identify antimicrobial susceptibility trends and provide data for the timely adaptation of empirical treatment guidelines. Starting in late 2009, the Study for Monitoring Antimicrobial Resistance Trends (SMART) has monitored the in vitro susceptibility profiles of Gram-negative bacilli causing UTIs and intra-abdominal infections. SMART has documented the high prevalence of antibiotic resistance in Asia [1]. This report summarises the susceptibility to commonly used antimicrobials among isolates causing UTIs in four tertiary care centres in Vietnam. Two hospitals in Ho Chi Minh City and two hospitals in Hanoi collected non-duplicate Gram-negative isolates during the period 2010–2011 from patients with UTI. A total of 341 UTI isolates were collected. Enterobacteriaceae accounted for the majority of the isolates (293/341; 85.9%). Escherichia coli (225/293; 76.8%) and Klebsiella pneumoniae (27/293; 9.2%) accounted for 86.0% of all Enterobacteriaceae. Identification and antimicrobial susceptibility testing using broth microdilution were performed at a central laboratory according to Clinical and Laboratory Standards Institute (CLSI) guidelines [2]. Susceptibility was categorised and quality control was performed following CLSI guidelines [3].
Extended-spectrum b-lactamase (ESBL) phenotypes among E. coli, K. pneumoniae, Klebsiella oxytoca and Proteus mirabilis isolates were determined according to CLSI guidelines [3]. Isolates were categorised as community-associated (CA) if collected <48 h after hospitalisation and as hospital-associated (HA) if collected 48 h after hospitalisation. Rates of susceptibility to 12 antimicrobial agents are presented in Table 1. For E. coli and K. pneumoniae, the most effective antibiotic in vitro was ertapenem, followed by amikacin, imipenem and piperacillin/tazobactam (TZP). Low susceptibility rates to most antimicrobials were observed for Pseudomonas aeruginosa (range 40–60%) and Acinetobacter baumannii (range 29–57%). Only ertapenem (92.5%) and imipenem (88.8%) had percent susceptible values that were acceptable against K. pneumoniae. In contrast, E. coli and K. pneumoniae, which accounted for 73.9% of the UTI pathogens in this study, displayed high rates of resistance to fluoroquinolones (ciprofloxacin and levofloxacin) and third- and fourth-generation cephalosporins, even higher than was reported recently from the Asia-Pacific region [4]. Pseudomonas aeruginosa and A. baumannii had typically higher rates of resistance to all drug classes than Enterobacteriaceae. Since these two species represented >12% of the Gramnegative bacilli in this study, their high resistance rates are quite alarming. Carbapenems are considered the treatment of choice for ESBL-positive organisms and resistance to this class is problematic for patient therapy [4]. Among the isolates with a determined environmental source of infection, 28.7% were CA and 70.0% were HA, and the ranking of species was similar in both patient populations. ESBL production was detected in 62.7% of E. coli and 44.4% of K. pneumoniae. The prevalence of both ESBL-positive Enterobacteriaceae and nonfermenters was higher among patients with HA UTIs compared with CA UTIs. The rate of ESBL-positive E. coli (63.9%) and K. pneumoniae (50.0%) in HA UTI was marginally higher than isolates from CA UTIs for E. coli but not for K. pneumoniae. The most
Table 1 In vitro susceptibilities (%) of Enterobacteriaceae and non-Enterobacteriaceae collected from patients with urinary tract infections in Vietnam during 2010–2011.a Organism (n)
SAM
AMK
CTX
CAZ
CFT
FOX
CIP
CEF
ERT
IPM
LVX
TZP
Enterobacteriaceae Escherichia coli (225) E. coli, ESBL + (141) Klebsiella pneumoniae (27) K. pneumoniae, ESBL + (12)
13.7 9.9 33.3 0.0
96.0 94.3 81.4 58.3
24.8 1.4 40.7 0.0
36.4 19.1 48.1 16.6
24 0.0 40.7 0.0
67.5 70.9 74.0 75.0
20.8 11.3 44.4 8.3
31.1 2.8 44.4 0.0
98.6 99.2 92.5 91.6
99.1 99.2 88.8 91.6
21.7 12.0 48.1 8.3
81.3 82.9 74.0 58.3
Non-fermenters Pseudomonas aeruginosa (30) Acinetobacter spp. (14)
–b 35.7
56.6 35.7
– 28.5
46.6 28.5
– 28.5
– –
40.0 35.7
40.0 28.5
– –
60.0 57.1
40.0 42.8
46.6 50.0
SAM, ampicillin/sulbactam; AMK, amikacin; CTX, ceftriaxone; CAZ, ceftazidime; CFT, cefotaxime; FOX, cefoxitin; CIP, ciprofloxacin: CEF, cefepime; ERT, ertapenem; IPM, imipenem; LVX, levofloxacin; TZP, piperacillin/tazobactam; ESBL, extended-spectrum b-lactamase. a Based on Clinical and Laboratory Standards Institute (CLSI) 2013 breakpoints [3]. b A dash indicates that no breakpoints exist for this species. http://dx.doi.org/10.1016/j.jgar.2014.04.003 2213-7165/ß 2014 Published by Elsevier Ltd on behalf of International Society for Chemotherapy of Infection and Cancer.
Please cite this article in press as: Thi Thanh Nga T, et al. In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J Global Antimicrob Resist (2014), http://dx.doi.org/10.1016/j.jgar.2014.04.003
G Model
JGAR-87; No. of Pages 2 2
Letter to the Editor / Journal of Global Antimicrobial Resistance xxx (2014) xxx–xxx
effective antibiotics against these two ESBL-positive species were ertapenem and imipenem (92–99% susceptible), amikacin (94.3% susceptible, E. coli only) and TZP (82.9% susceptible, E. coli only). Rates of susceptibility to all other agents tested were <75% for both species. Susceptibility to amikacin and TPZ among ESBL-positive K. pneumoniae (both 58.3%) was lower compared with ESBL-positive E. coli. Although these data from Vietnam are somewhat limited, this study is among the first to give a snapshot of the burden of antibiotic resistance among Gram-negative isolates from UTI in this country and highlights increasing resistance among ESBL-producing Enterobacteriaceae in Vietnam and the AsiaPacific region, as has been reported elsewhere [1,4–6]. The current data showed alarmingly high ESBL rates (45%) in Vietnam compared with the Asia/Pacific region average of 28.2%. The study was not designed to demonstrate causality and the two large cities may not accurately represent the entire country. However, in view of excessive antibiotic consumption as reported in a surveillance study from Vietnam [274 defined daily doses (DDD) per 100 bed-days in Vietnam compared with 58 DDD per 100 bed-days in The Netherlands in the same year], and with second- and third-generation cephalosporins and fluoroquinolones used as workhorse antibiotics, the likelihood of disproportionate antibiotic consumption causing selection pressure and antibiotic resistance cannot be disregarded, as illustrated in previous studies [7]. Therefore, utilisation of these agents should be closely monitored to ensure appropriateness of use. In view of the high prevalence of ESBL-producing isolates and a relatively limited selection of antibiotics to treat multiresistant infections, this study emphasises the need for enhanced infection control and antibiotic stewardship programmes. Treatment regimens driven by guidelines, coupled with infection control measures, are needed to reduce the adverse consequences of antimicrobial misuse. Funding This study was funded by Merck & Co., Inc. (protocol number CLI-486). Competing interest DJB and REB served as scientific advisors or consultants to Merck and received research support from Merck to conduct this study; PN and TGP are affiliated with MSD, a subsidiary of Merck & Co., Inc. All other authors declare no competing interests. Ethical approval Not required. Acknowledgments The authors thank all SMART investigators for their participation in this programme.
References [1] Hawser SP, Bouchillon SK, Hoban DJ, Badal RE, Hsueh PR, Paterson DL. Emergence of high levels of extended-spectrum-b-lactamase-producing Gram-negative bacilli in the Asia-Pacific region: data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program, 2007. Antimicrob Agents Chemother 2009;53:3280–4. [2] Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. 9th ed. Wayne, PA: CLSI; 2012, Document M07-A9. [3] Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-third informational supplement. Wayne, PA: CLSI; 2013, Document M100-S23. [4] Lu PL, Liu YC, Toh HS, Lee YL, Liu YM, Ho CM, et al. Epidemiology and antimicrobial susceptibility profiles of Gram-negative bacteria causing urinary tract infections in the Asia-Pacific region: 2009-2010 results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Int J Antimicrob Agents 2012;40(Suppl.):S37–43. [5] Meier S, Weber R, Zbinden R, Ruef C, Hasse B. Extended-spectrum b-lactamaseproducing Gram-negative pathogens in community-acquired urinary tract infections: an increasing challenge for antimicrobial therapy. Infection 2011;39:333–40. [6] Hsu LY, Tan TY, Tam VH, Kwa A, Fisher DA, Koh TH. Network for Antimicrobial Resistance Surveillance (Singapore). Surveillance and correlation of antibiotic prescription and resistance of Gram-negative bacteria in Singaporean hospitals. Antimicrob Agents Chemother 2010;54:1173–8. [7] Global Antibiotic Resistance Partnership. First report on antibiotic use and resistance in Vietnam hospitals in 2008–2009. A report from the Ministry of Health of the Socialist Republic of Vietnam in collaboration with the Global Antibiotic Resistance Partnership and Oxford University Clinical Research Unit, http://benhnhietdoi.vn/data/files/documents/Report_on_antibiotics_use_and_ resistance_in_15_hospitals_in_2008-2009.pdf [accessed 29.04.14].
Tran Thi Thanh Nga Cho Ray Hospital, Ho Chi Minh City, Viet Nam Tran Thi Lan Phuong Viet Duc Hospital, Hanoi, Viet Nam Tran My Phuong Binh Dan Hospital, Ho Chi Minh City, Viet Nam Doan Mai Phuong Bach Mai Hospital, Hanoi, Viet Nam Douglas J. Biedenbach* International Health Management Associates, Inc., Schaumburg, IL, USA Prashant Narang MSD Pharmaceuticals Pvt. Ltd., India Trong Giao Phan MSD Pharmaceuticals Pvt. Ltd., Viet Nam Robert E. Badal International Health Management Associates, Inc., Schaumburg, IL, USA *Corresponding author. Present address: 2122 Palmer Drive, Schaumburg, IL 60173, USA. Tel.: +1 847 303 5003/847 664 9426; fax: +1 847 303 5601 E-mail address: [email protected] (D.J. Biedenbach). 21 October 2013
Please cite this article in press as: Thi Thanh Nga T, et al. In vitro susceptibility of Gram-negative isolates from patients with urinary tract infections in Vietnam: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J Global Antimicrob Resist (2014), http://dx.doi.org/10.1016/j.jgar.2014.04.003