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ORIGINAL ARTICLE
Year : 2009  |  Volume : 46  |  Issue : 4  |  Page : 318-322
 

Comparison of in vitro activities of ceftazidime, piperacillin-tazobactam, and cefoperazone-sulbactam, and the implication on empirical therapy in patients with cancer


Tata Memorial Hospital, Mumbai, India

Date of Web Publication9-Sep-2009

Correspondence Address:
K Prabhash
Tata Memorial Hospital, Mumbai
India
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Source of Support: None, Conflict of Interest: None


Read associated Guest Editorial: Empirical versus theoretical with this article

DOI: 10.4103/0019-509X.55552

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 » Abstract 

Background: Infection is a common cause of morbidity and mortality in cancer patients. In most of these cases empirical treatment is provided because the focus of infection is not identified. Empiric antibiotics provided to these patients are based on isolates, sensitivity, and on guidelines. Here we have compared three antibiotics recommended as empirical treatment by the Infectious Disease Society of America (IDSA). Aims: To compare the three antibiotic sensitivities for gram negative isolates at our institute. Objective: To choose the optimal antibiotic as the empirical treatment for cancer patients developing infections. Materials and Methods: We collected the data on isolates and antibiotic sensitivity patterns of isolates for ceftazidime, piperacillin + tazobactum, and cefoperazone from the medical oncology department. We subsequently compared the sensitivity of these three antibiotics. Statistical Methods: The isolates were mapped using the WHONET 5.4 software. The analysis was conducted using SPSS 15.0 for Windows. McNemar Chi-square test was used to compare the sensitivity percentages between any two antibiotics. The agreement between the antibiotic and the gold standard was calculated using the Kappa statistic. Two tailed p values were reported. Results: The results showed that there was a difference among sensitivities for these antibiotics. It appears that the sensitivity of ceftazidime was inferior to the two other antibiotics. Also cefoperazone has better sensitivity as compared to piperacillin + tazobactum. Conclusion: In spite of these three antibiotics being recommended by IDSA our data suggest that it should not be followed blindly and local sensitivity data is important for formulating institutional guidelines for using antibiotics.


Keywords: Antibiotics, sensitivity patterns, empirical treatment, oncology


How to cite this article:
Prabhash K, Medhekar A, Biswas S, Kurkure P, Nair R, Kelkar R. Comparison of in vitro activities of ceftazidime, piperacillin-tazobactam, and cefoperazone-sulbactam, and the implication on empirical therapy in patients with cancer. Indian J Cancer 2009;46:318-22

How to cite this URL:
Prabhash K, Medhekar A, Biswas S, Kurkure P, Nair R, Kelkar R. Comparison of in vitro activities of ceftazidime, piperacillin-tazobactam, and cefoperazone-sulbactam, and the implication on empirical therapy in patients with cancer. Indian J Cancer [serial online] 2009 [cited 2019 Sep 18];46:318-22. Available from: http://www.indianjcancer.com/text.asp?2009/46/4/318/55552



 » Introduction Top


Infections are a common cause of increased morbidity and mortality among cancer patients. Patients with cancer are predisposed to infections as a result of immunosuppression due to the underlying illness, chemotherapeutic agents, as well as surgical procedures that violate protective barriers. Treatment of such infections depends on the establishment of a focus of infection and an appropriate therapy. However in a fair number of patients, no identifiable focus is present even after extensive evaluation. It is therefore necessary to have an empirical treatment protocol for such patients.

This study is aimed at identifying the possible etiologic agents and determining their antibiotic sensitivity pattern, thereby allowing formulation of a reasonable initial empirical therapy regimen. The Infectious Disease Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN) have published guidelines for the use of empirical agents in cancer patients with infections, which include imipenam-cilastatin and meropenam as monotherapy, or cefepime and ceftazidime with or without an aminoglycoside, or piperacillin-tazobactam with an aminoglycoside. [1],[2] Through this study we have compared the in vitro efficacy of ceftazidime, pipercillin-tazobactam, and cefoperazone-sulbactam against gram-negative organisms isolated from cancer patients at our institute, over a period of one year, to try and form an empirical antibiotic policy for our institute.


 » Materials and Methods Top


This was a retrospective study conducted at a tertiary care cancer hospital in Mumbai. The in vitro sensitivity of isolates, from samples received from adult inpatients admitted in the Medical Oncology Services of our institute, was analyzed. All the samples sent during the year 2007 were evaluated. Of these, gram-negative bacterial isolates from only those samples that represented infection were considered. These samples included peripheral blood, blood drawn through catheters, catheter tips, fluid from sterile body sites, urine, and pus swabs from patients with an appropriate clinical syndrome. The in vitro sensitivity of these isolates against cefoperazone-sulbactam, piperacillin-tazobactam, and ceftazidime was studied. The antibiotic sensitivity was determined by means of the disc diffusion method, using the Clinical and Laboratory Standards Institute (CLSI) standards. Extended Spectrum Beta-Lactamase (ESBL) production was confirmed by CLSI recommendations using cephalosporin-clavulunate combination discs. A difference of >5 mm between the zone diameter of either of the cephalosporin discs and their respective cephalosporin-clavulunate discs was taken to be the phenotypic confirmation of ESBL production. We used cefotaxime (30 µg), ceftazidime (30 µg), and ceftazidime / clavulanic acid (30 µg / 10 µg) discs for ESBL determination.

Statistical methods

The isolates were mapped using the WHONET 5.4 software. The analysis was conducted using SPSS 15.0 for Windows. The Mc Nemar chi-square test was used to compare the sensitivity percentages between any two antibiotics. The agreement between the antibiotics and the gold standard was calculated using the Kappa statistic. Two tailed p values were reported.


 » Results Top


A total of 990 isolates were obtained from all samples sent from the Medical Oncology services. Of these 671 were gram-negative bacteria and 547 were from samples that represented infection. Identical isolates from a single patient were considered only once. Thirty-one isolates were thus excluded from the analysis and a total of 516 isolates were analyzed.

A majority of the isolates (332 representing 64.34%) were from blood and catheter-related samples. Samples from the respiratory tract, sputum and bronchoalveolar lavage, and pleural fluid accounted for 133 isolates (25.78%). There were 30 urinary isolates (5.81%). The rest of the isolates were from sterile sites, pus, and drain fluid. The distribution of the samples from which these 516 isolates were obtained is given in [Table 1].

The majority of the bacteria were non-lactose fermenters (320 representing 62.02% of the isolates). Of these the Pseudomonas species accounted for 210 isolates (40.7%). There were 196 (38.98%) isolates from the Enterobacteriacea group of organisms. The distribution of the bacterial species is given in [Table 2].

ESBL production was detected in 100 isolates (19.38% of all isolates). These included 50 isolates of Klebsiella pneumoniae (64.94% of Klebsiella pneumoniae isolates), 45 of E.Coli (51.72% of E.Coli isolates), two Enterobacter cloacae isolates, and one each of Kleibsiella oxytoca, Pseudomonas aerugenosa , and Enterobacter aerogenes .

The antibiotic sensitivity patterns revealed that for all bacterial isolates, cefoperazone-sulbactam was sensitive against 58.3% of the isolates, piperacillin-tazobactam against 48.1%, and ceftazidime against 40.1%. The distribution of the sensitivity patterns of the three antibiotics against the various bacterial groups is given in [Table 3].

The sensitivity pattern for the Enterobacteriacea group revealed that 67.9% of isolates were sensitive to cefoperazone-sulbactam, 45.4% to piperacillin-tazobactam and 26.5% to ceftazidime.

Among the non-lactose fermenters, 52.5% isolates were sensitive to cefoperazone-sulbactam, 49.6% to piperacillin-tazobactam, and 48.4% to ceftazidime.

For the Pseudomonas species, Piperacillin-tazobactam was sensitive against 58.4%, cefoperazone-sulbactam against 57.4%, and ceftazidime against 53.1 % isolates.

After analysis using McNemar Chi square test it was found that there was statistically significant difference in the activity of cefoperazone-sulbactam and ceftazidime against all gram-negative isolates, isolates of the Enterobacteriaceae group, ESBL producing isolates, and non-lactose fermenters, and the results favored a better response with cefoperazone-sulbactam. However, the activity of both antibiotics was comparable against the Pseudomonas isolates. The details of the results are given in [Table 4].

When the activity of pipercillin-tazobactam was compared with that of cefoperazone-sulbactam, the susceptibility of all isolates considered together, the isolates from the Enterobacteriaceae group and those of ESBL producers were better for cefoperazone-sulbactam and this reached statistical significance. The activity against non-lactose fermenters and pseudomonas species was comparable. A similar result was obtained when the activity of piperacillin-tazobactam was compared with that of ceftazidime, with better susceptibility to piperacillin-tazobactam. The detailed results are given in [Table 5] and [Table 6].


 » Discussion Top


Infections in patients with cancer are an important cause of mortality and morbidity. Most deaths from acute leukemia and half the deaths in lymphoma can be directly attributed to infections. The use of highly effective and intensive chemotherapeutic regimens also subject patients with solid tumors to the risk of death due to infection. The use of 'early empirical' therapy has reduced the mortality in patients with leukemia and bacteremia from 85% to 20-36% over the last five decades. The use of this 'empirical' therapy in afebrile neutropenic patients promises to reduce mortality even further. [3]

The IDSA and the NCCN guidelines for management of infections in patients with cancer do not include the cefoperazone-sulbactam combination, but do advocate both ceftazidime as monotherapy or aminoglycoside and piperacillin-tazobactam with an aminoglycoside. [1],[2] This may be due to the fact that this combination is not available in the United States. However, in countries where the drug administration agencies have approved of this combination, its use should be considered.

At our institute, empirical antibiotic policy includes the use of piperacillin-tazobactam, cefoperazone-sulbactam or carbapenam as monotherapy or in combination with an aminoglycoside (preference being given to 2 drug therapy).

The use of empirical therapy relies on the premise that the most probable infective organisms are sensitive to the regimen employed. This in turn is determined by the prevailing antibiotic sensitivity pattern in the health care facility and on the results of prevalence studies performed elsewhere (if patterns are unavailable). The growing resistance to antibiotics among various bacterial isolates is a cause of concern and supports the need for frequent revision of empirical therapy protocols. Moreover, the prescribed guidelines from various organizations might not be applicable to all geographic locales.

Studies comparing the activities of various beta-lactam and beta-lactam inhibitor combinations have shown variable results. Generally the efficacy of pipercillin-tazobactam and cefoperazone-sulbactam has been better than most other combinations studied. Studies in India have shown piperacillin-tazobactam to be better than cefoperazone-sulbactam especially against Pseudomonas sp, Klebsiella sp, and E. coli . [4],[5],[6] However, our study produced results to the contrary. This study found that cefoperazone-sulbactam was comparable if not more effective against all the bacterial groups as compared to piperacillin-tazobactam (only among pseudomonas sp was the activity of piperacillin-tazobactam marginally better than cefoperazone-sulbactam, although not statistically significant). We considered isolates that were in the intermediate range to be resistant. Even if these isolates were considered to be sensitive, the activity of both the antibiotics would be comparable if not favoring cefoperazone-sulbactam. There are similar studies that have reached this conclusion. [7],[8]

The reason for such an occurrence could be the fact that piperacillin-tazobactam is much more commonly utilized as an empirical agent in our institute. This could have resulted in selection pressure for development of resistance. The other reason might lie in the beta-lactamase inhibitor present in the combination. One particular advantage of using sulbactam containing combinations is that sulbactam itself has an inherent activity against some isolates of Acinetobacter baumannii . Sulbactam containing combinations have not demonstrated strong selective pressures for ESBL producing Enterobacteriaceae . In contrast to clavulanate, sulbactam does not induce class I (Amp C) chromosomal beta-lactamases in Enterobacteriaceae . [9]

For Acinetobacter strains, cefoperazone-sulbactam has been compared with the imipenam-cilastatin combination and has shown an efficacy that is not statistically different. [10] Its efficacy in the setting of oncology services, both for the treatment of febrile neutropenia as empirical therapy, [11],[12] as well as severe infections in cancer patients, [13],[14],[15] has been studied with favorable results.

Considering the comparable in vitro efficacy of cefoperazone-sulbactam and piperacillin-tazobactam, thought should be given to the use of this agent. The activity of ceftazidime was evidently poor as compared to the other two antibiotics. The magnitude of difference (40.1% vs. 48.1-58.3% and 43.02% vs. 58.91-66.67% - if intermediate strains are also considered as sensitive) between the efficacy of ceftazidime and the other two antibiotics makes monotherapy with ceftazidime an inappropriate choice for empirical therapy in our setting. However, the high degree of resistance (33.37-59.1%) to all the three tested antibiotics is a cause of concern, and monotherapy with these agents would be inappropriate. This might render the use of carbapenams as the only satisfactory empirical agent for monotherapy at our institute.

 
 » References Top

1.Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T et al ; 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002:34:730-51.  Back to cited text no. 1    
2.Segal BH, Baden LR, Brown AE, Casper C, Dubberke E, Freifeld AG et al ; Prevention and treatment of cancer related infections. J Natl Compr Canc Netw 2008;6:122-74.  Back to cited text no. 2    
3.Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL et al . Infections in patients with cancer (pg 533-41); Harrison's Principles of Internal Medicine. 17 th ed. U.S.A: McGraw-Hill; 2008;533-41.  Back to cited text no. 3    
4.Mohanty S, Singhal R, Sood S, Dhawan B, Das BK, Kapil A. Comparative in vitro activity of beta-lactam/beta-lactamase inhibitor combinations against gram negative bacteria. Indian J Med Res 2005;122:425-8.  Back to cited text no. 4    
5.Gupta V, Datta P, Agnihotri N, Chander J. Comparative in vitro activities of seven new beta-lactams, alone and in combination with beta-lactamase inhibitors, against clinical isolates resistant to third generation cephalosporins. Braz J Infect Dis 2006;10:22-5.  Back to cited text no. 5    
6.Chitnis SV, Chitnis V, Sharma N, Chitnis DS. Current status of drug resistance among gram-negative bacilli isolated from admitted cases in a tertiary care centre. J Assoc Physicians India 2003;51:28-32.  Back to cited text no. 6    
7.Kumarasinghe G, Chow C, Chiu C, Cheong YM. In vitro activity of cefoperazone-sulbactam: Singapore experience. Southeast Asian J Trop Med Public Health 1996;27:734-7.  Back to cited text no. 7    
8.Wang H, Chen MJ, On Behalf Of China Nosocomial Pathogens Resistance Surveillance Study Group. [Changes of antimicrobial resistance among nonfermenting gram-negative bacilli isolated from intensive care units from 1994 to 2001 in China] Zhonghua Yi Xue Za Zhi 2003;83:385-90.  Back to cited text no. 8    
9.Akova M. Sulbactam-containing beta-lactamase inhibitor combinations. Clin Microbiol Infect 2008;14:185-8.  Back to cited text no. 9    
10.Choi JY, Kim CO, Park YS, Yoon HJ, Shin SY, Kim YK et al . Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter bacteremia. Yonsei Med J 2006;47:63-9.  Back to cited text no. 10    
11.Winston DJ, Bartoni K, Bruckner DA, Schiller GJ, Territo MC. Randomized comparison of sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile granulocytopenic patients. Clin Infect Dis 1998;26:576-83.  Back to cited text no. 11    
12.Bodey G, Abi-Said D, Rolston K, Raad I, Whimbey E. Imipenem or cefoperazone-sulbactam combined with vancomycin for therapy of presumed or proven infection in neutropenic cancer patients. Eur J Clin Microbiol Infect Dis 1996;15:625-34.  Back to cited text no. 12    
13.Mitrokhin SD. [Sulperazone in the treatment of severe infections in patients with cancer]. Antibiot Khimioter 2003;48:26-9.  Back to cited text no. 13    
14.Mitrokhin SD, Avilova ND. [Three-year experience with the use of cefoperazone/sulbactam (sulperazone) in the treatment of hospital-acquired infections in an oncologic hospital]. Antibiot Khimioter 2006;51:14-7.  Back to cited text no. 14    
15.Bodey GP, Miller P, Ho DH. In vitro assessment of sulbactam plus cefoperazone in the treatment of bacteria isolated from cancer patients. Diagn Microbiol Infect Dis 1989;12:209-14.  Back to cited text no. 15    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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