|Year : 2016 | Volume
| Issue : 6 | Page : 229-233
Antimicrobial activities of cefoperazone-sulbactam in comparison to cefoperazone against clinical organisms from medical centers in Taiwan
Tsung-Ta Chiang1, Hung-Jen Tang2, Cheng-Hsun Chiu3, Te-Li Chen4, Mao-Wang Ho5, Chen-Hsiang Lee6, Wang-Huei Sheng7, Ya-Sung Yang1
1 Department of Internal Medicine, National Defense Medical Center, Division of Infectious Diseases and Tropical Medicine, Taipei, Taiwan, China
2 Department of Medicine, Chi Mei Medical Center; Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, China
3 Department of Pediatrics, Chang Gung Children's Hospital and Chang Gung University, Taoyuan, Taiwan, China
4 National Defense Medical Center, The Graduate Institute of Life Sciences, Taipei, Taiwan, China
5 Department of Internal Medicine, Division of Infectious Diseases, China Medical University Hospital, Taichung, Taiwan, China
6 Department of Internal Medicine, Kaohsiung Medical Center, Division of Infectious Diseases, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, China
7 Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, China
|Date of Submission||03-Jul-2016|
|Date of Decision||19-Sep-2016|
|Date of Acceptance||18-Oct-2016|
|Date of Web Publication||21-Dec-2016|
Department of Internal Medicine, National Defense Medical Center, Division of Infectious Diseases and Tropical Medicine, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Taipei 11490, Taiwan
Source of Support: None, Conflict of Interest: None
Background: The multidrug-resistant Gram-negative bacteria (MDRGNBs) have emerged as important pathogens recently. Cefoperazone-sulbactam is active against a great proportion of those MDRGNBs. However, the susceptibilities data of cefoperazone-sulbactam are lacking in Taiwan. Object: This study was conducted to evaluate the susceptibilities data of cefoperazone-sulbactam aganist commonly encountered clinical pathogens in Taiwan. Materials and Methods: 2272 isolates were collected from various clinical specimens from five centers in Taiwan in 2012. The agar dilution method was used to evaluate the susceptibility of the isolated pathogens to cefoperazone and cefoperazone-sulbactam. Result: cefoperazone-sulbactam showed better activity against various GNBs, including MDRGNBs and part of carbapenem-resistant isolates tested compared to cefoperazone alone. Conclusion: Cefoperazone-sulbactam is active against most commonly encountered clinical pathogens, including MDRGNBs and part of carbapenem-esistant A. baumannii complex. It can be a potentially therapeutic agent for treating infections caused by these pathogens in Taiwan.
Keywords: Antibiotic, cefoperazone, resistance, susceptibility, sulbactam
|How to cite this article:|
Chiang TT, Tang HJ, Chiu CH, Chen TL, Ho MW, Lee CH, Sheng WH, Yang YS. Antimicrobial activities of cefoperazone-sulbactam in comparison to cefoperazone against clinical organisms from medical centers in Taiwan. J Med Sci 2016;36:229-33
|How to cite this URL:|
Chiang TT, Tang HJ, Chiu CH, Chen TL, Ho MW, Lee CH, Sheng WH, Yang YS. Antimicrobial activities of cefoperazone-sulbactam in comparison to cefoperazone against clinical organisms from medical centers in Taiwan. J Med Sci [serial online] 2016 [cited 2022 Dec 8];36:229-33. Available from: https://www.jmedscindmc.com/text.asp?2016/36/6/229/196365
| Introduction|| |
Cefoperazone has a broad-spectrum activity against both Gram-positive cocci (GPCs) and Gram-negative bacteria (GNBs). , However, antimicrobial resistance developed through various mechanisms, including β-lactamases produced by GNBs in recent decades. , Sulbactam has been shown to enhance the in vitro spectrum of cefoperazone, , and the combination is active against a great proportion of many clinical pathogens including multidrug-resistant GNBs (MDRGNBs).  These include extended-spectrum beta-lactamases (ESBLs) producing Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii.  Of noted, the sulbactam contained in this drug is also potentially active against A. baumannii,  which has become an emerging clinical pathogen. 
The antimicrobial susceptibilities of the microorganisms are crucial for the selection of appropriate antimicrobial therapy. Unfortunately, there were fewer data of the susceptibility of cefoperazone-sulbactam against commonly encountered clinical pathogens and the above-mentioned MDRGNBs in Taiwan recently. The most updated data were collected about 5 years ago.  Therefore, this study is conducted to evaluate the susceptibilities of cefoperazone-sulbactam in comparison to cefoperazone against various clinical isolates collected from medical centers in Taiwan.
| Methods|| |
The clinical isolates were collected from five medical centers in Taiwan, including Lin Kou Chang Gung Memorial Hospital and Taipei Veterans General Hospital in the north; China Medical University Hospital in the middle region; and Chi Mei Hospital and Kaohsiung Chang Gung Memorial Hospital in the south [Table 1].
Isolates were collected from various clinical specimens from five centers in 2012, which included Group A and B Streptococcus, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus (MSSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, P. aeruginosa, and A. baumannii [Table 1].
Antimicrobial susceptibility tests
The agar dilution method was performed in accordance with the guidance of Clinical and Laboratory Standards Institute (CLSI).  The combination ratio of cefoperazone and sulbactam for tests was 1:1.  Sulbactam combined with cefoperazone in a 1:1 ratio was purchased from TTY Biopharm, Taiwan.
The susceptibility breakpoints for cefoperazone-sulbactam are not elucidated in the current CLSI guidelines; hence, the CLSI breakpoint criteria  for cefoperazone alone were applied for cefoperazone-sulbactam for comparison purpose only. E. coli ATCC 25922 and 35218, P. aeruginosa ATCC 27853 were used as control strains.
To assess differences, the Chi-square test with Yate's correction or Fisher's exact test was used. A P < 0.05 was considered statistically significant. All the analyses were processed with Statistical Package for the Social Sciences software version 18.0 (SPSS, Chicago, IL, USA).
| Results|| |
A total of 476 GPC and 1796 GNB clinical isolates were collected. These included Group A Streptococcus (1.71%), Group B Streptococcus (4.48%), S. pneumoniae (3.82%), MSSA (10.65%), E. coli (11.00%), K. pneumoniae (10.17%), E. cloacae (7.83%), S. marcescens (5.37%), P. mirabilis (7.66%), P. aeruginosa (7.83%), Stenotrophomonas maltophilia (3.83%), Salmonella spp. (6.56%), and A. baumannii (16.51%). Antimicrobial susceptibilities of cefoperazone alone and in combination with sulbactam against GPCs are shown in [Table 2] and those against GNBs are shown in [Table 3]. Cefoperazone exhibited potent activity against most Streptococcus spp. and MSSA. In GNBs, cefoperazone had limited activity against most Enterobacteriaceae and nonfermenting GNBs. The overall susceptibilities of cefoperazone against important GNBs, including E. coli, K. pneumoniae, E. cloacae, P. mirabilis, P. aeruginosa, and other Enterobacteriaceae, were ranging from 5.8% to 76.4%. However, the susceptibilities against A. baumannii and S. maltophilia were low: 0.27% and 5.8%, respectively.
|Table 2: Antimicrobial susceptibilities of cefoperazone and cefoperazone-sulbactam against Gram-positive bacteria|
Click here to view
|Table 3: Antimicrobial susceptibilities of cefoperazone and cefoperazone-sulbactam against Gram-negative bacteria|
Click here to view
The combination of sulbactam and cefoperazone showed better activity against various GNBs tested compared to cefoperazone alone [Table 3]. In addition, the combination also exhibited better activity against A. baumannii than cefoperazone alone (71.2% vs. 0.27%).
The susceptibilities of cefoperazone-sulbactam against MDRGNBs are shown in [Table 4]. In ESBL-producing E. coli and ESBL-producing K. pneumoniae, the susceptibilities were 65.9% and 60.7%. And those against carbapenem-resistant A. baumannii and P. aeruginosa were 62.2% and 0%.
|Table 4: Antimicrobial susceptibilities of cefoperazone and cefoperazone-sulbactam against multidrug-resistant Gram-negative bacteria|
Click here to view
| Discussion|| |
This study demonstrated the antimicrobial susceptibilities of cefoperazone alone and in combination of sulbactam against various clinical pathogens. Cefoperazone-sulbactam showed great activities against those commonly encountered clinical pathogens. In MDRGNBs, especially Enterobacteriaceae, P. aeruginosa, and A. baumannii isolates, cefoperazone-sulbactam demonstrated good antimicrobial activities, except those were carbapenem resistant and which may provide another therapeutic option for treating MDRGNBs.
In recent years, the emergence of antimicrobial resistance has become a worldwide problem. ESBL-producing Enterobacteriaceae, P. aeruginosa, and A. baumannii are frequently encountered MDRGNBs. In Taiwan, the annual prevalence rate of ESBL-producing E. coli and K. pneumoniae isolates doubled from 2008 to 2010 (5.2%-11.5%, and 4.5%-12.1%, respectively). , This significantly limited the choice of antimicrobial agents. Carbapenems were regarded as one of very limited choices for treating ESBL-producing Enterobacteriaceae infection. , In the current result, cefoperazone-sulbactam exhibited good activity against most Enterobacteriaceae, including those ESBL-producing strains. In addition, P. aeruginosa and Acinetobacter spp. are common pathogens of hospital-acquired infections, which are frequently resistant to multiple antibiotics. Recently, the antimicrobial resistance of P. aeruginosa was increasing including carbapenems.  The overall susceptibility of P. aeruginosa to cefepime, piperacillin-tazobactam, and imipenem was 71%, 83.9%, and 74.7%, respectively.  Furthermore, A. baumannii complex even exhibited higher resistances to cefepime, piperacillin-tazobactam, and imipenem, ranging from 58% to 68% (60.9%, 68.4%, and 58.7%, respectively).  In the current study, cefoperazone-sulbactam demonstrated good activity against P. aeruginosa and A. baumannii complex. By the irreversibly block the effects of several β-lactamases, cefoperazone-sulbactam also showed good activities against ESBLs such as TEM, SHV, and CTX-M.  The addition of sulbactam makes the full potential of cefoperazone to against Pseudomonas species and Enterobacteriaceae, even encountered those harboring plasmid-mediated transferable enzymes and extended-spectrum enzymes. 
In comparison to other countries of Asia-pacific region, cefoperazone-sulbactam exhibited better activities against those MDRGNBs in Taiwan, except for carbapenem-resistant P. aeruginosa and A. baumannii complex.,, In recent published data, the antimicrobial resistances of cefoperazone-sulbactam to E. coli and K. pneumoniae ranged from 2% to 35% and 4% to 17% in Asian countries other than Taiwan. ,, The ESBL producers ranged 9.7%-59.9% and 9.6%-61.3% among E. coli and K. pneumoniae isolates in Asia-pacific region. ,, The resistances of cefoperazone-sulbactam to those ESBL-producing E. coli and K. pneumoniae ranged 3.3%-71% and 8.6%-28.8%. ,,, The resistances of cefoperazone-sulbactam to P. aeruginosa and A. baumannii complex ranged 11.7%-24.2% and 26.3%-50%, respectively. ,,, As the emerging prevalence of carbapenem-resistant P. aeruginosa and A. baumannii complex ranging 10.4%-56.9% and 22.2%-86.7% among all those isolates, ,,, the resistances of cefoperazone-sulbactam to those carbapenem-resistant isolates mentioned above were even higher: 55.3%-69.8%. ,,,
| Conclusion|| |
Cefoperazone-sulbactam is active against most commonly encountered clinical pathogens in Taiwan. Moreover, it is active against MDR pathogens, such as ESBL-producing E. coli and K. pneumoniae and part of carbapenem-resistant A. baumannii complex, which can be a potentially therapeutic agent for treating infections caused by these pathogens.
Financial support and sponsorship
This work was supported by grants from the Tri-Service General Hospital (TSGH-C103-125, TSGH-C104-119, TSGH-105-113, and DV104-09), the Ministry of Science and Technology (103-2314-B-016-039 and 104-2314-B-016-051), Taiwan.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Brogden RN, Carmine A, Heel RC, Morley PA, Speight TM, Avery GS. Cefoperazone: A review of its in vitro
antimicrobial activity, pharmacological properties and therapeutic efficacy. Drugs 1981;22:423-60.
Matsubara N, Minami S, Muraoka T, Saikawa I, Mitsuhashi S. In vitro
antibacterial activity of cefoperazone (T-1551), a new semisynthetic cephalosporin. Antimicrob Agents Chemother 1979;16:731-5.
Kuo HY, Wang FD, Yen YF, Lin ML, Liu CY. In vitro
activities of piperacillin or cefoperazone alone and in combination with beta-lactamase inhibitors against gram-negative bacilli. New Microbiol 2009;32:49-55.
Kuo SC, Chang SC, Wang HY, Lai JF, Chen PC, Shiau YR, et al.
Emergence of extensively drug-resistant Acinetobacter baumannii
complex over 10 years: Nationwide data from the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program. BMC Infect Dis 2012;12:200.
Williams JD. Beta-Lactamase inhibition and in vitro
activity of sulbactam and sulbactam/cefoperazone. Clin Infect Dis 1997;24:494-7.
Akova M. Sulbactam-containing beta-lactamase inhibitor combinations. Clin Microbiol Infect 2008;14 Suppl 1:185-8.
Wang FD, Lin ML, Lee WS, Liu CY. In vitro
activities of beta-lactam antibiotics alone and in combination with sulbactam against Gram-negative bacteria. Int J Antimicrob Agents 2004;23:590-5.
Tseng SH, Lee CM, Lin TY, Chang SC, Chang FY. Emergence and spread of multi-drug resistant organisms: Think globally and act locally. J Microbiol Immunol Infect 2011;44:157-65.
Sheng WH, Wang JT, Li SY, Lin YC, Cheng A, Chen YC, et al.
Comparative in vitro
antimicrobial susceptibilities and synergistic activities of antimicrobial combinations against carbapenem-resistant Acinetobacter
species: Acinetobacter baumannii
genospecies 3 and 13TU. Diagn Microbiol Infect Dis 2011;70:380-6.
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-First Informational Supplement: CLSI Document M100-S21. Wayne: Clinical and Laboratory Standards Institute; 2011.
Liu YM, Chen YS, Toh HS, Huang CC, Lee YL, Ho CM, et al. In vitro
susceptibilities of non-Enterobacteriaceae
isolates from patients with intra-abdominal infections in the Asia-Pacific region from 2003 to 2010: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Int J Antimicrob Agents 2012;40 Suppl 1:S11-7.
Hsueh PR, Badal RE, Hawser SP, Hoban DJ, Bouchillon SK, Ni Y, et al.
Epidemiology and antimicrobial susceptibility profiles of aerobic and facultative Gram-negative bacilli isolated from patients with intra-abdominal infections in the Asia-Pacific region: 2008 results from SMART (Study for Monitoring Antimicrobial Resistance Trends). Int J Antimicrob Agents 2010;36:408-14.
Huang CC, Chen YS, Toh HS, Lee YL, Liu YM, Ho CM, et al.
Impact of revised CLSI breakpoints for susceptibility to third-generation cephalosporins and carbapenems among Enterobacteriaceae
isolates in the Asia-Pacific region: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2002-2010. Int J Antimicrob Agents 2012;40 Suppl 1:S4-10.
Paterson DL. Recommendation for treatment of severe infections caused by Enterobacteriaceae
producing extended-spectrum beta-lactamases (ESBLs). Clin Microbiol Infect 2000;6:460-3.
Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae
: An emerging public-health concern. Lancet Infect Dis 2008;8:159-66.
Hu FP, Guo Y, Zhu DM, Wang F, Jiang XF, Xu YC, et al.
Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014. Clin Microbiol Infect 2016;22 Suppl 1:S9-14.
Yamamoto A, Yamasaki K. Evaluation of antibiotic treatments for urinary tract infections in the elderly, especially regarding the effect on extended spectrum ß-lactamase producing (ESBL-) Escherichia coli
: A comparison between meropenem and alternatives. Nihon Ronen Igakkai Zasshi 2015;52:153-61.
Dhanoa A, Rajasekaram G, Lean SS, Cheong YM, Thong KL. Endemicity of Acinetobacter calcoaceticus
-baumannii complex in an intensive care unit in Malaysia. J Pathog 2015;2015:789265.
Mendes RE, Mendoza M, Banga Singh KK, Castanheira M, Bell JM, Turnidge JD, et al.
Regional resistance surveillance program results for 12 Asia-Pacific nations (2011). Antimicrob Agents Chemother 2013;57:5721-6.
Jean SS, Coombs G, Ling T, Balaji V, Rodrigues C, Mikamo H, et al.
Epidemiology and antimicrobial susceptibility profiles of pathogens causing urinary tract infections in the Asia-Pacific region: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2010-2013. Int J Antimicrob Agents 2016;47:328-34.
Karagöz A, Sunnetcioglu M, Ceylan MR, Bayram Y, Yalcin G, Kocak N, et al.
Characterisation of drug resistance of nosocomial ESBL-producing E. coli
isolates obtained from a Turkish university hospital between 2009 and 2012 by pulsed field gel electrophoresis and antibiotic resistance tests. Infez Med 2016;24:24-31.
Mohanty S, Maurya V, Gaind R, Deb M. Phenotypic characterization and colistin susceptibilities of carbapenem-resistant of Pseudomonas aeruginosa
spp. J Infect Dev Ctries 2013;7:880-7.
Chung DR, Song JH, Kim SH, Thamlikitkul V, Huang SG, Wang H, et al.
High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia. Am J Respir Crit Care Med 2011;184:1409-17.
Huh K, Kim J, Cho SY, Ha YE, Joo EJ, Kang CI, et al.
Continuous increase of the antimicrobial resistance among gram-negative pathogens causing bacteremia: A nationwide surveillance study by the Korean Network for Study on Infectious Diseases (KONSID). Diagn Microbiol Infect Dis 2013;76:477-82.
Lai CC, Lee K, Xiao Y, Ahmad N, Veeraraghavan B, Thamlikitkul V, et al
. High burden of antimicrobial drug resistance in Asia. J Glob Antimicrob Resist 2014;2:141-7.
Pei G, Mao Y, Sun Y. In vitro
activity of minocycline alone and in combination with cefoperazone-sulbactam against carbapenem-resistant Acinetobacter baumannii
. Microb Drug Resist 2012;18:574-7.
Shamaeva SK, Portnyagina US, Edelstein MV, Kuzmina AA, Maloguloval S, Varfolomeeva NA. Results of monitoring metallo-beta-lactamase-producing strains of Pseudomonas aeruginosa
in a multi-profile hospital. Wiad Lek 2015;68:546-8.
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Model-Informed Drug Development of New Cefoperazone Sodium and Sulbactam Sodium Combination (3:1): Pharmacokinetic/Pharmacodynamic Analysis and Antibacterial Efficacy Against Enterobacteriaceae
| ||Xi-Wei Ji, Xiao Zhu, Yun Li, Feng Xue, Isabelle Hui San Kuan, Qing-Feng He, Xiang-Rui Meng, Xiao-Qiang Xiang, Yi-Min Cui, Bo Zheng |
| ||Frontiers in Pharmacology. 2022; 13 |
|[Pubmed] | [DOI]|
||Optimal Dose of Cefoperazone-Sulbactam for Acute Bacterial Infection in Patients with Chronic Kidney Disease
| ||Chien-Ming Chao, Chih-Cheng Lai, Chen-Hsiang Lee, Hung-Jen Tang |
| ||Antibiotics. 2022; 11(5): 610 |
|[Pubmed] | [DOI]|
||Therapeutic Effectiveness of Cefoperazone for Community-Acquired Pneumonia and Associated Factors in a Tertiary Care Hospital, Vietnam
| ||Cua Ngoc Le, Duong Trung Nguyen, Supreecha Kaewsawat, Charuai Suwangbamrung, Patthanasak Khammaneechan |
| ||Journal of Pharmacy and Nutrition Sciences. 2021; 11: 20 |
|[Pubmed] | [DOI]|
||Clinical effectiveness of cefoperazone-sulbactam vs. piperacillin-tazobactam for the treatment of pneumonia in elderly patients
| ||Chun-Ta Huang, Chia-Hung Chen, Wei-Chih Chen, Yao-Tung Wang, Chih-Cheng Lai, Pin-Kuei Fu, Li-Kuo Kuo, Chin-Ming Chen, Wen-Feng Fang, Chih-Yen Tu, Shih-Chi Ku |
| ||International Journal of Antimicrobial Agents. 2021; : 106491 |
|[Pubmed] | [DOI]|
||Cefoperazone/sulbactam: New composites against multiresistant gram negative bacteria?
| ||Yee-Huang Ku,Wen-Liang Yu |
| ||Infection, Genetics and Evolution. 2021; : 104707 |
|[Pubmed] | [DOI]|
||Clinical Efficacy and Safety of Cefoperazone–Sulbactam in Treatment of Intra-Abdominal Infections: A Systematic Review and Meta-Analysis
| ||Shao-Huan Lan,Chien-Ming Chao,Shen-Peng Chang,Li-Chin Lu,Chih-Cheng Lai |
| ||Surgical Infections. 2021; |
|[Pubmed] | [DOI]|
||In Vitro Antimicrobial Activity of Various Cefoperazone/Sulbactam Products
| ||Ming-Jen Sheu,Chi-Chung Chen,Ying-Chen Lu,Bo-An Su,Chun-Cheng Zhang,Shu-Shen Wang,Yin-Ching Chuang,Hung-Jen Tang,Chih-Cheng Lai |
| ||Antibiotics. 2020; 9(2): 77 |
|[Pubmed] | [DOI]|
||Randomized Noninferiority Trial of Cefoperazone-Sulbactam versus Cefepime in the Treatment of Hospital-Acquired and Healthcare-Associated Pneumonia
| ||Jien-Wei Liu,Yen-Hsu Chen,Wen-Sen Lee,Jung-Chung Lin,Ching-Tai Huang,Hsi-Hsun Lin,Yung-Ching Liu,Yin-Ching Chuang,Hung-Jen Tang,Yao-Shen Chen,Wen-Chien Ko,Min-Chi Lu,Fu-Der Wang |
| ||Antimicrobial Agents and Chemotherapy. 2019; 63(8) |
|[Pubmed] | [DOI]|
||The impact of inoculum size on the activity of cefoperazone-sulbactam against multidrug resistant organisms
| ||Ping-Chin Chang,Chi-Chung Chen,Ying Chen Lu,Chih-Cheng Lai,Hui-Ling Huang,Yin-Ching Chuang,Hung-Jen Tang |
| ||Journal of Microbiology, Immunology and Infection. 2017; |
|[Pubmed] | [DOI]|