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Letter to the Editor

Reply to Zhou and Wu, “Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam”

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
Jien-Wei Liu
aDivision of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
bChang Gung University College of Medicine, Taoyuan, Taiwan
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Yen-Hsu Chen
cDivision of Infectious Diseases, Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
dCollege of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Wen-Sen Lee
eDivision of Infectious Diseases, Department of Internal Medicine, Wan Fang Medical Center, Taipei, Taiwan
fDepartment of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
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Jung-Chung Lin
gDivision of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Ching-Tai Huang
bChang Gung University College of Medicine, Taoyuan, Taiwan
hDivision of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
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Hsi-Hsun Lin
iGeneral Research Center, Department of Medical Research, Taipei Veterans General Hospital and Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Yung-Ching Liu
fDepartment of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
jDivision of Infectious Diseases, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan
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Yin-Ching Chuang
kDepartment of Internal Medicine, Chi Mei Hospital, Liouying, Taiwan
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Hung-Jen Tang
lDepartment of Medicine, Chi Mei Medical Center, Tainan, Taiwan
mDepartment of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
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Yao-Shen Chen
nSchool of Medicine, National Yang-Ming University, Taipei, Taiwan
oDepartment of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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Wen-Chien Ko
pDepartment of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
qCollege of Medicine, National Cheng Kung University, Tainan, Taiwan
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Min-Chi Lu
rDepartment of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
sDepartment of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan
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Fu-Der Wang
nSchool of Medicine, National Yang-Ming University, Taipei, Taiwan
tDivision of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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DOI: 10.1128/AAC.02028-19
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REPLY

We thank Drs. Zhou and Wu for their interest in our recent publication entitled “Randomized noninferiority trial of cefoperazone-sulbactam versus cefepime in the treatment of hospital-acquired and health care-associated pneumonia” (1) and appreciate comments they made on it. The recruited patients in this trial were allocated to subpopulations for intent-to treat (ITT), per-protocol (PP), and safety analyses.

All patients (n = 166) who received at least one dose of either cefoperazone-sulbactam or cefepime were included for safety analysis. Of those, 12 patients were excluded before entering the ITT subpopulation (n = 154) because of either violation of the study protocol or withdrawal from the study under the patient’s or their family’s request, and therefore, no follow-up information was available for outcome evaluations. Given these missing outcome data, we admit that the ITT analysis in this article would be better defined as a modified ITT with an explicit statement about postrandomization exclusions (2, 3).

As antibiotic therapies for a minimum of 7 days for hospital-acquired pneumonia (HAP) and health care-associated pneumonia (HCAP) have been widely accepted and recommended (4, 5), only recruited patients who underwent antibiotic therapy for ≥7 days rather than all the patients in the ITT subpopulation were included for clinical success (cure or improvement) evaluation at the test-of-cure visit, as was shown in Table 2 (1). Table 1 summarized baseline characteristics of patients who were evaluable for clinical success in the ITT subpopulation.

Permutated block randomization with an allocation ratio of 1:1 generating the random assignment of subjects was performed before this study. An independent statistician was responsible for generating randomization codes, and each random assignment was put in a sealed, opaque, and numbered envelop. The recruited patients were randomly assigned by a sequentially numbered envelope to different treatment arms to receive either intravenous cefoperazone-sulbactam or cefepime therapy. The study design and experiment were definitively and completely randomized. With the exception of the body mass index (BMI [kg/m2]) (cefoperazone-sulbactam arm, 20.1 ± 3.6 versus cefepime arm, 21.4 ± 4.6; P = 0.048), statistically nonsignificant differences in baseline characteristics were found between patients from the ITT subpopulation allocated to different treatment arms and subjected to clinical success evaluation. Of note, between patients from the PP subpopulation allocated to the cefoperazone-sulbactam arm and the cefepime arm and included for clinical success evaluation, all baseline demographic and clinical characteristics, including BMI (cefoperazone-sulbactam arm, 20.0 ± 3.4 versus cefepime arm, 21.5 ± 4.5; P = 0.058), were not statistically significantly different. Given this, it is plausible that there was a type I error for alpha = 0.05 for comparison of the BMIs between different treatment arms in the ITT analysis (6).

Based on the difference in BMI between treatment arms for clinical success evaluation in the ITT analysis, Zhou and Wu raised the question of whether the difference in BMI might lead to meaningfully different antibiotic concentrations in these patients’ blood streams, thereby affecting the mortality rate. Overweight and obese individuals were reported to be at significantly higher risk of acquisition of pneumonia but were at lower risk of pneumonia mortality, which was referred to as “obesity survival paradox” (7); the paradoxical phenomenon has not been fully understood, and proposed explanations included that the metabolic reserves in overweight and obese individuals suffering pneumonia better counteract the increased catabolic stresses (7). Of note, in previously published studies, BMIs were categorized (e.g., underweight, normal BMI, obesity, and morbid obesity) for assessment of the clinical outcomes of the pneumonia patients (7). One meta-analysis revealed that an increase in 5 kg/m2 of BMI reduced pneumonia mortality by 5% (relative risk of 0.95, with 95% confidence level of 0.93 to 0.98; P < 0.01) (7). It is not evident that the difference in clinical outcome between the cefepime and the cefoperazone-sulbactam arms in the ITT analysis in our series was confounded by the difference in BMI of 1.3 kg/m2 (1); the BMIs of both arms belonged to the same categorized one. Results of clinical success rates in both the ITT and PP analyses in this study evaluating therapeutic effects against HAP/HCAP supported the conclusion that cefoperazone-sulbactam was noninferior to cefepime. Among the overall adverse events, serious adverse events (15.2% versus 5.7%; P = 0.224) and mortality rate (37.8% versus 18.2%; P = 0.281) were found to be higher in the cefoperazone-sulbactam arm than in the cefepime arm, and yet, they were statistically nonsignificantly different.

In summary, our data suggested that cefoperazone-sulbactam is noninferior to cefepime in treating HAP/HCAP; we concur with Zhou and Wu that the safety profile of cefoperazone-sulbactam needs to be consolidated by further study with a larger sample size.

FOOTNOTES

  • This is a response to a letter by Zhou and Wu (https://doi.org/10.1128/AAC.01942-19).

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Reply to Zhou and Wu, “Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam”
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 Jan 2020, 64 (2) e02028-19; DOI: 10.1128/AAC.02028-19

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Reply to Zhou and Wu, “Be Careful with Adverse Events Caused by Cefoperazone-Sulbactam”
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 Jan 2020, 64 (2) e02028-19; DOI: 10.1128/AAC.02028-19
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