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To evaluate the in vitro activity of ampicillin-sulbactam and cefoperazone-sulbactam against A. baumannii using the broth disk elution testing, a total of 150 A. baumannii isolates were collected from across China between January 2019 and January 2021, including 51 carbapenem-susceptible and 99 carbapenem-resistant isolates. Broth disk elution (BDE) and the broth microdilution (BMD) method were performed for all strains. The concentration range of the BDE was 10/10 µg/mL, 20/20 µg/mL, and 30/30 µg/mL for ampicillin-sulbactam, and 37.5/15 µg/mL, 75/30 µg/mL, 112.5/45 µg/mL, and 150/60 µg/mL for cefoperazone-sulbactam, respectively. Compared with BMD, the BDE results of ampicillin-sulbactam and cefoperazone-sulbactam showed a categorical agreement of 83.3% (125/150) and 95.3% (143/150), with minor errors of 16.7% (25/150) and 4.7% (7/150), respectively. No major error or very major errors were detected. The sensitivity differences by BDE of carbapenem-resistant A. baumannii (CRAb) to different concentrations of ampicillin-sulbactam showed statistically significant (p < 0.017), while those to cefoperazone-sulbactam at 37.5/15 µg/mL, 75/30 µg/mL, and 112.5/45 µg/mL were significant (p < 0.008). However, no significant difference in sensitivity was observed between 112.5/45 µg/mL and 150/60 µg/mL (p > 0.008). In conclusion, the BDE is a reliable and convenient method to detect the in vitro activity of cefoperazone-sulbactam against A. baumannii, and the results could serve as a clinical reference value when deciding whether or not to use high-dose sulbactam for the treatment of A. baumannii infections. [ABSTRACT FROM AUTHOR]

In an era of increasing antibiotic resistance among pathogens, the treatment options for infectious diseases are diminishing. One of the clinical groups especially vulnerable to this threat are patients who are hospitalized in intensive care units due to ventilator-associated pneumonia caused by multidrug-resistant/extensively drug-resistant Gram-negative bacteria. In order to prevent the exhaustion of therapeutic options for this life-threatening condition, there is an urgent need for new pharmaceuticals. Novel β-lactam antibiotics, including combinations of cephalosporins with β-lactamase inhibitors, are proposed as a solution to this escalating problem. The unique mechanism of action, distinctive to this new group of siderophore cephalosporins, can overcome multidrug resistance, which is raising high expectations. In this review, we present the summarized results of clinical trials, in vitro studies, and case studies on the therapeutic efficacy of cefoperazone-sulbactam, ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol in the treatment of ventilator-associated pneumonia. We demonstrate that treatment strategies based on siderophore cephalosporins and combinations of β-lactams with β-lactamases inhibitors show comparable or higher clinical efficacy than those used with classic pharmaceuticals, like carbapenems, colistin, or tigecycline, and are often associated with a lower risk of adverse events. [ABSTRACT FROM AUTHOR]

Background: The drug resistance of carbapenem-resistant Acinetobacter baumannii bloodstream infections (CRAB-BSI), especially hospital-acquired infections, has promoted their rapid and vast spread. It is necessary to use reliable methods to establish better prediction models. According to Cox proportional hazards regression, a nomogram was established. Methods: A retrospective cohort study among patients who were diagnosed with CRAB-BSI was performed from January 2020 to December 2022. Univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors regarding CRAB-BSI. Then, nomograms were used to calculate the area under the curve (AUC), C-index, and calibration curve to determine the predictive accuracy and discriminability. Decision curve analysis (DCA) was employed to further confirm the clinical effectiveness of the nomogram. Results: A total of 98 cases were included in the comparison between the 28-day mortality group consisting of 32 patients and the 28-day survival group with 66 patients. The use of cefoperazone-sulbactam was significantly higher among patients who survived than among those who died. Univariable analysis revealed that factors such as primary diagnosis, time to inadequate antimicrobial therapy, and high serum creatinine and procalcitonin (PCT) levels were more prevalent in the mortality group. However, only primary diagnosis, time to inadequate antimicrobial therapy, and high PCT levels emerged as statistically significant risk factors for death in multivariate analysis and were used to construct the nomogram. The nomogram validation exhibited excellent performance. Conclusions: The nomogram was sufficiently accurate to predict the risk and prognostic factors of CRAB-BSI, allowing for individualized clinical decisions for future clinical work. The cefoperazone-sulbactam did have an effect, but more studies are needed to interpret it. [ABSTRACT FROM AUTHOR]

In an era of increasing antibiotic resistance among pathogens, the treatment options for infectious diseases are diminishing. One of the clinical groups especially vulnerable to this threat are patients who are hospitalized in intensive care units due to ventilator-associated pneumonia caused by multidrug-resistant/extensively drug-resistant Gram-negative bacteria. In order to prevent the exhaustion of therapeutic options for this life-threatening condition, there is an urgent need for new pharmaceuticals. Novel β-lactam antibiotics, including combinations of cephalosporins with β-lactamase inhibitors, are proposed as a solution to this escalating problem. The unique mechanism of action, distinctive to this new group of siderophore cephalosporins, can overcome multidrug resistance, which is raising high expectations. In this review, we present the summarized results of clinical trials, in vitro studies, and case studies on the therapeutic efficacy of cefoperazone-sulbactam, ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol in the treatment of ventilator-associated pneumonia. We demonstrate that treatment strategies based on siderophore cephalosporins and combinations of β-lactams with β-lactamases inhibitors show comparable or higher clinical efficacy than those used with classic pharmaceuticals, like carbapenems, colistin, or tigecycline, and are often associated with a lower risk of adverse events.

BackgroundKounis syndrome is a hypersensitive coronary artery disease caused by the body's exposure to allergens, which is induced by various drugs and environmental factors. This entity has been described primarily in isolated case reports and case series. We report a case of type III Kounis syndrome caused by cefoperazone-sulbactam.Case presentationA 79-year-old man who received an infusion of cefoperazone-sulbactam in Respiratory Department of our hospital for recurrent infections. 28 minutes later, he developed skin flushing of the trunk and extremities, soon followed by loss of consciousness and shock. With antianaphylaxis, pressor therapy, and fluid rehydration, the patient was admitted to the ICU for treatment. During which, he experienced recurrent ventricular fibrillation and a progressive increase in troponin I levels. The ECG of the patient showed that the ST segment elevation of lead II, III, avF, and V3R–V5R was 0.10–0.20 MV. An urgent coronary angiography showed an in-stent thrombosis in the middle part of the right coronary artery, occlusion of the distal flow with TIMI grade 0. The diagnosis was type III Kounis syndrome with cardiogenic shock. Despite aggressive treatment, the patient died on day 7 after ICU admission.ConclusionKunis syndrome is a life-threatening disease, and therefore allergic reactions in patients with a history of cephalosporin allergy and coronary stent implantation should be considered and treated promptly.

ABSTRACT Cefoperazone-sulbactam (SCF)-resistant Pseudomonas aeruginosa poses a big challenge in the use of SCF to treat infection caused by the pathogen. We have recently shown exogenous nitrite-enabled killing of naturally and artificially evolved Pseudomonas aeruginosa strains (AP-RCLIN-EVO and AP-RLAB-EVO, respectively) by SCF. However, the underlying mechanism is unknown. Here, reprogramming metabolomics was adopted to investigate how nitrite enhanced the SCF-mediated killing efficacy. Nitrite-reprogrammed metabolome displayed an activated pyruvate cycle (P cycle), which was confirmed by elevated activity of pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase. The activated P cycle provided NADH for the electron transport chain and thereby increased reactive oxygen species (ROS), which potentiated SCF to kill AP-RCLIN-EVO and AP-RLAB-EVO. The nitrite-enabled killing of AP-RCLIN-EVO and AP-RLAB-EVO by SCF was inhibited by PDH inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but promoted by ROS promoter Fe3+. SCF alone could not induce ROS, but SCF-mediated killing efficacy was enhanced by ROS. In addition, the present study demonstrated that nitrite repressed antioxidants, which were partly responsible for the elevated ROS. These results reveal a nitrite-reprogrammed metabolome mechanism by which AP-RCLIN-EVO and AP-RLAB-EVO sensitivity to SCF is elevated. IMPORTANCE Antibiotic-resistant Pseudomonas aeruginosa has become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. Understanding antibiotic resistance mechanisms and developing novel control measures are highly appreciated. We have recently shown that a reduced nitrite-dependent NO biosynthesis contributes to cefoperazone-sulbactam (SCF) resistance, which is reverted by exogenous nitrite, in both naturally and artificially evolved P. aeruginosa strains (AP-RCLIN-EVO and AP-RLAB-EVO, respectively). However, the mechanism is unknown. The present study reports that the nitrite-enabled killing of AP-RCLIN-EVO and AP-RLAB-EVO by SCF is attributed to the promoted production of reactive oxygen species (ROS). Nitrite activates the pyruvate cycle to generate NADH for the electron transport chain, which in turn promotes ROS generation. Nitrite-potentiated SCF-mediated killing is decreased by pyruvate dehydrogenase inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but increased by ROS promoter Fe3+. Furthermore, SCF-mediated killing is promoted by H2O2 in a dose-dependent manner. In addition, the combination of nitrite and H2O2 greatly enhances SCF-mediated killing. These results not only disclose a nitrite-ROS-potentiated SCF-mediated killing, but also show SCF-mediated killing is dependent upon ROS.

Siripen Kanchanasuwan,1 Narongdet Kositpantawong,1 Kamonnut Singkhamanan,2 Thanaporn Hortiwakul,1 Boonsri Charoenmak,1 Nwabor Ozioma F,1,3 Yohei Doi,4,5 Sarunyou Chusri1,2 1Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, 90110, Thailand; 2Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Songkhla, 90110, Thailand; 3Excellence Research Laboratory on Natural Products, Division of Biological Science, Faculty of Science and Natural Product Research Center of Excellence, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand; 4Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 5Department of Microbiology, Fujita Health University, Aichi, JapanCorrespondence: Sarunyou Chusri Tel +66-89-7340446Fax +66-74-281457Email sarunyouchusri@hotmail.comIntroduction: The efficacy of adjunctive therapy with cefoperazone-sulbactam (CEP-SUL) for ventilator-associated pneumonia (VAP) due to carbapenem-resistant A. baumannii (CRAB) is unclear.Methods: We retrospectively analyzed the therapeutic effect of adding CEP-SUL to standard regimens for VAP due to CRAB. Patients with VAP due to CRAB strains that were susceptible to CEP-SUL were enrolled into the study. The patients were divided into two groups: those who receive cefoperazone-sulbactam (CEP-SUL+), and those who did not receive cefoperazone-sulbactam (CEP-SUL). Mortality rates and resource utilization of these two groups were compared. Factors associated with mortality were explored.Results: Eighty patients were enrolled into the study, 52 CEP-SUL+ and 28 CEP-SUL–. The baseline characteristics of the two groups were comparable, except for median Acute Physiology and Chronic Health Evaluation (APACHE) II score which was significantly higher for CEP-SUL+. Thirty-day, and in-hospital mortality rates for CEP-SUL+ were significantly lower than CEP-SUL– with values of 35%, 39% and 61%, 68%, for CEP-SUL+ and CEP-SUL–, respectively. The survival rate for CEP-SUL+ was significantly higher compared with CEP-SUL– (P < 0.001). The number of hospital days, ventilator days since diagnosis of VAP and hospital costs were lower for CEP-SUL+.Conclusion: Overall results suggested that patients with VAP due to CRAB strains who received adjunctive therapy with CEP-SUL had lower mortality rates and resource utilization compared with CEP-SUL–.Keywords: outcome, cefoperazone-sulbactam, ventilator-associated pneumonia, carbapenem-resistant Acinetobacter baumannii

The optimal dosage of cefoperazone-sulbactam for patients with chronic kidney disease (CKD) remains unclear. This study aimed to investigate two treatment strategies of cefoperazone-sulbactam–2 g/2 g twice daily and adjusted dose according to renal function for patients with CKD. A total of 155 patients with CKD received cefoperazone-sulbactam either at a dose of 2 g/2 g twice daily (study group) or adjusted according to renal function (control group) for the treatment of acute bacterial infection. The primary outcome was the clinical response rate at day 14 and the secondary outcomes included treatment failure and all-cause death. The study group had a higher clinical response rate (80.0% vs. 65.0%) and a lower treatment failure rate (4.0% vs. 23.8%) as compared with the control group. Further multivariable analysis showed that compared with the control group, the study group had a higher clinical response rate (adjusted OR = 4.02; 95% CI, 1.49–10.81) and lower treatment failure rate (adjusted OR = 0.06; 95% CI, 0.01–0.28). In addition, no significant difference in all-cause mortality was observed between the study and the control group (adjusted OR = 1.95; 95% CI, 0.57–6.66). Finally, no significant difference was observed between the study and the control group in the risk of the adverse events (AEs)–diarrhea (p = 0.326), eosinophilia (p = 1.000), prolonged PT (p = 0.674), alteration in renal function (p = 0.938) and leukopenia (n = 0.938). In conclusion, cefoperazone-sulbactam at a dose of 2 g/2 g twice daily could achieve better clinical efficacy than the reduced dosage regimen. Additionally, this dosage did not increase the risk of AE compared to the reduced dose. Therefore, cefoperazone-sulbactam at a dose of 2 g/2 g twice daily is an effective and safe regimen for acute bacterial infection in patients with CKD. [ABSTRACT FROM AUTHOR]

Background: In this systematic review and meta-analysis, we aimed to assess the clinical efficacy and safety of cefoperazone-sulbactam against alternative antibiotics in the treatment of intra-abdominal infections. Methods: The PubMed, Cochrane, Web of Science, Ovid Medline, and CKNI databases were searched for relevant articles up to November 25, 2020. The primary outcome was clinical efficacy rate, and the secondary outcomes were microbiologic eradication rate, mortality rate, and adverse event (AE) risk. Results: Twelve studies involving 1,674 patients were included. Overall, the clinical efficacy rate of cefoperazone-sulbactam and comparators was 87.7% and 81.7%, respectively, and cefoperazone-sulbactam was associated with a higher clinical efficacy rate than that the comparator (odds ratio [OR] 1.98; 95% confidence interval [CI] 1.31-3.00; I2 = 36%). Additionally, cefoperazone-sulbactam was associated with a lower clinical failure rate (OR 0.40; 95% CI 0.28-0.57; I2 = 0) and a higher clinical cure rate (OR 1.54; 95% CI 1.17-2.03; I2 = 0) than the comparators. Cefoperazone-sulbactam was associated with a higher microbiologic eradication rate than the comparator (OR 2.54; 95% CI 1.72-3.76; I2 = 0). Finally, there was no significant difference between cefoperazone-sulbactam and the comparators in terms of mortality rate (OR 090; 95% CI 0.38-2.16; I2 = 0) and AE risk (OR 1.07; 95% CI 0.74-1.55; I2 = 0). Conclusions: The clinical efficacy and safety of cefoperazone-sulbactam were similar to those of alternative antibiotics in the treatment of intra-abdominal infections. Therefore, cefoperazone-sulbactam could be recommended as an effective and safe antibiotic for treating intra-abdominal infections. [ABSTRACT FROM AUTHOR]

aim of this study was to compare the usefulness of cefoperazone-sulbactam and that of piperacillin-tazobactam in the treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Methods: This retrospective study included the adult patients receiving cefoperazone-sulbactam or piperacillin-tazobactam against HAP/VAP in nine hospitals in Taiwan from March 1, 2018 to May 30, 2019. Primary outcome was clinical cure rate. Results: A total of 410 patients were enrolled. Among them, 209 patients received cefoperazone-sulbactam and 201 patients received piperacillin-tazobactam. Overall, cefoperazone-sulbactam group had similar distribution of age, sex, or SOFA scores as piperacillin-tazobactam group. However, cefoperazone-sulbactam had higher comorbidity score and disease severity than piperacillin-tazobactam group (Charlson score: 6.5 ± 2.9 vs 5.7 ± 2.7, p < 0.001; APACHE II score: 21.4 ± 6.2 vs 19.3 ± 6.0, p = 0.002). Regarding clinical outcomes, no significant difference in clinical cure and failure rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical cure rate: 80.9% vs 80.1% and clinical failure rate: 17.2% vs 18.4%, p = 0.943). Moreover, no significant difference in clinical effectiveness and ineffectiveness rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical effective rate: 80.9% vs 80.6% and clinical ineffective rate: 17.7% vs 18.9%, p = 0.711). The all-cause mortality rates of the cefoperazone-sulbactam and piperacillin-tazobactam groups were similar (23.9% vs 20.9%, p = 0.48). After adjustment of Charlson score and APACHE II score, the similarities in these clinical outcomes did not change in overall patients and patients with HAP or VAP. Conclusion: For treating adult patients with nosocomial pneumonia, cefoperazone-sulbactam was as effective as piperacillin-tazobactam. [ABSTRACT FROM AUTHOR]

Chih-Cheng Lai,1 Chi-Chung Chen,2,3 Ying-Chen Lu,3 Yin-Ching Chuang,2,4 Hung-Jen Tang5,6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Food Science, National Chiayi University, Chiayi, Taiwan; 4Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 5Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan; 6Department of Health and Nutrition, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan Background: This study aimed to investigate the in vitro activity of cefoperazone–sulbactam against carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and to evaluate the antibiotic resistance mechanisms of these bacteria. Materials and methods: In total, 21 isolates of carbapenem-resistant P. aeruginosa and 15 isolates of carbapenem-resistant A. baumannii with different pulsed-field gel electrophoresis types were collected for assessment of the in vitro antibacterial activities of cefoperazone and cefoperazone–sulbactam and the associated resistance mechanisms of the bacteria. Results: For carbapenem-resistant P. aeruginosa, the minimum inhibitory concentration (MIC) value and antibiotic susceptibility rate were similar for cefoperazone and cefoperazone–sulbactam (at 1:1 and 2:1 ratios). In contrast, for carbapenem-resistant A. baumannii, the MIC values, including the MIC range, MIC that inhibited 50% of isolates (MIC50) and MIC that inhibited 90% of isolates (MIC90), were reduced after treatment with sulbactam and cefoperazone. We screened resistance genes, including VIM-2, OXA-2 and OXA-10, in 21 carbapenem-resistant P. aeruginosa isolates. Only one (4.8%) of the isolates showed expression of VIM-2, and neither the OXA-2 nor the OXA-10 gene was detected. However, 20 (95.2%) isolates among the carbapenem-resistant P. aeruginosa isolates selected for oprD sequencing showed the phenomenon of nucleotide substitution or deletion. Among 15 carbapenem-resistant A. baumannii isolates, we found that ten (66.7%) isolates had concomitant expression of the OXA-23 and ISAba1-OXA-23 genes, and six (40.0%) isolates had expression of the OXA-24-like gene. All 15 isolates had OXA-51-like gene expression, and only 1 (6.7%) isolate had ISAba1-OXA-51-like gene expression. None of the isolates contained the IMP-1, IMP-8, KPC, NDM, VIM-1 or OXA-48 genes. Conclusion: The in vitro antibacterial activity of cefoperazone against carbapenem-resistant A. baumannii can be enhanced by adding sulbactam to cefoperazone, but the addition does not affect carbapenem-resistant P. aeruginosa. This significant difference can be explained by the different resistance mechanisms of carbapenem-resistant A. baumannii and P. aeruginosa. Keywords: cefoperazone–sulbactam, Acinetobacter baumannii, Pseudomonas aeruginosa

The optimal dosage of cefoperazone-sulbactam for patients with chronic kidney disease (CKD) remains unclear. This study aimed to investigate two treatment strategies of cefoperazone-sulbactam–2 g/2 g twice daily and adjusted dose according to renal function for patients with CKD. A total of 155 patients with CKD received cefoperazone-sulbactam either at a dose of 2 g/2 g twice daily (study group) or adjusted according to renal function (control group) for the treatment of acute bacterial infection. The primary outcome was the clinical response rate at day 14 and the secondary outcomes included treatment failure and all-cause death. The study group had a higher clinical response rate (80.0% vs. 65.0%) and a lower treatment failure rate (4.0% vs. 23.8%) as compared with the control group. Further multivariable analysis showed that compared with the control group, the study group had a higher clinical response rate (adjusted OR = 4.02; 95% CI, 1.49–10.81) and lower treatment failure rate (adjusted OR = 0.06; 95% CI, 0.01–0.28). In addition, no significant difference in all-cause mortality was observed between the study and the control group (adjusted OR = 1.95; 95% CI, 0.57–6.66). Finally, no significant difference was observed between the study and the control group in the risk of the adverse events (AEs)–diarrhea (p = 0.326), eosinophilia (p = 1.000), prolonged PT (p = 0.674), alteration in renal function (p = 0.938) and leukopenia (n = 0.938). In conclusion, cefoperazone-sulbactam at a dose of 2 g/2 g twice daily could achieve better clinical efficacy than the reduced dosage regimen. Additionally, this dosage did not increase the risk of AE compared to the reduced dose. Therefore, cefoperazone-sulbactam at a dose of 2 g/2 g twice daily is an effective and safe regimen for acute bacterial infection in patients with CKD.

Tianshui Niu,1 TingTing Xiao,1 Lihua Guo,1 Wei Yu,2 Yunbo Chen,1 Beiwen Zheng,1 Chen Huang,1 Xiao Yu,1 Yonghong Xiao1 1Collaborative Initiative Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China; 2Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310003, China Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a rapidly emerging, life-threatening nosocomial infection. This study aimed to explore the risk factors, clinical features, antimicrobial therapy, and outcomes of CRAB bloodstream infections (BSIs).Methods: This is a retrospective, comparative analysis of data from patients with A. baumannii BSI, treated from 2012 to 2015 at a tertiary teaching hospital. Risk factors associated with CRAB BSI and factors associated with the 28-day mortality were evaluated using logistic analyses.Results: Data from 293 patients with confirmed A. baumannii BSI were included; 242 (82.6%) patients had CRAB BSI and 51 (17.4%) patients had non-CRAB BSI. Risk factors significantly associated with CRAB BSI were a previous intensive care unit (ICU) stay (P=0.029), cefoperazone–sulbactam use (P=0.030), and carbapenem use (P=0.004). Among 236 patients with A. baumannii BSI who were evaluable at 28 days after receiving antibacterial therapy, there were 86 deaths. Factors associated with the 28-day mortality were ICU stay after BSI (P=0.040), readmission within 90 days (P=0.029), Acute Physiology and Chronic Health Evaluation II (APACHE II) score at diagnosis >19 (P=0.012), tigecycline therapy (P=0.021), presence of septic shock (P=0.029), and multiple organ failure (P=0.016). Death rates in patients treated with tigecycline were 53.5% vs 24.1% in patients treated with other agents. Among 186 patients with CRAB BSI evaluable at 28 days, 84 patients died. The associated risk factors were an ICU stay after BSI (P=0.036), APACHE II score >19 at diagnosis (P=0.002), presence of septic shock (P=0.030), and multiple organ failure (P=0.007).Conclusion: This study demonstrated that an ICU stay and cefoperazone–sulbactam or carbapenem use were seen to be the risk factors associated with the development of CRAB BSI. Critical illness and tigecycline therapy were significantly associated with higher mortality of patients with A. baumannii BSI. Keywords: Acinetobacter baumannii, carbapenem-resistant, bloodstream infection, cefoperazone–sulbactam, tigecycline

Chih-Cheng Lai,1 Chi-Chung Chen,2,3 Ying-Chen Lu,3 Tsuey-Pin Lin,4 Yin-Ching Chuang,2,5 Hung-Jen Tang4,6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, 2Department of Medical Research, Chi Mei Medical Center, Tainan, 3Department of Food Science, National Chiayi University, Chiayi, 4Department of Health and Nutrition, Chia-Nan University of Pharmacy and Science, 5Department of Internal Medicine, Chi Mei Medical Center, Liouying, 6Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan Objectives: This study aims to assess the in vitro activity of different cefoperazone–sulbactam ratios against different multidrug-resistant organisms (MDROs).Materials and methods: Minimum inhibitory concentrations (MICs) and susceptibility rates of cefoperazone, sulbactam and cefoperazone–sulbactam at fixed ratios of 2:1, 1:1 and 1:2 against 344 MDRO clinical isolates, including extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (n=58), ESBL-producing Klebsiella pneumoniae (n=58), carbapenem-resistant Enterobacteriaceae (n=57), carbapenem-resistant Pseudomonas aeruginosa (n=49) and carbapenem-resistant Acinetobacter baumannii (n=122), were measured.Results: Combined treatment with sulbactam and cefoperazone resulted in decreased MIC50 values across all MDROs, as well as decreases in most MIC90 values, except for carbapenem-resistant Enterobacteriaceae and carbapenem-resistant P. aeruginosa (MIC90 values remained >64 mg/L). Susceptibility rates of treatment with cefoperazone alone against all MDROs were much lower than that of cefoperazone–sulbactam combination (all P

• 19545 Gram-negative isolates were collected from medical centers located worldwide. • 82.0–94.4% of Enterobacterales (91.5% overall) were susceptible to cefoperazone-sulbactam at ≤16 mg/L. • 59.5–84.6% of P. aeruginosa (77.8% overall) were susceptible to cefoperazone-sulbactam at ≤16 mg/L. • Resistance rates varied widely and were generally higher in eastern Europe. • Cefoperazone-sulbactam was among the most active compounds in vitro. To evaluate the antimicrobial activities of cefoperazone-sulbactam and comparator agents tested against a large collection of clinical isolates of Gram-negative organisms. A total of 19 545 Gram-negative organisms were collected from medical centers located in western Europe (W-EUR; n = 10 626), eastern Europe and the Mediterranean region (E-EUR; n = 4029), the Asia-Pacific region (APAC; n = 2491), and Latin America (LATAM; n = 2399) in 2015–2016 and susceptibility tested by reference broth microdilution methods. Overall, 91.5% of Enterobacterales were susceptible (≤16 mg/L) to cefoperazone-sulbactam, with susceptibility rates ranging from 82.0% (E-EUR) to 94.4% (W-EUR); overall susceptibility to cefoperazone-sulbactam, piperacillin-tazobactam, imipenem, and ceftriaxone was 91.5%, 85.4%, 90.5%, and 72.1%, respectively. Among Pseudomonas aeruginosa isolates, cefoperazone-sulbactam susceptibility rates were higher in W-EUR, APAC, and LATAM (83.0–84.6%) compared to E-EUR (59.5%). Susceptibility to piperacillin-tazobactam, imipenem, and ceftazidime was 78.3%, 76.2%, and 82.0% in W-EUR; 52.3%, 43.5%, and 57.4% in E-EUR; 83.5%, 80.1%, and 84.5% in APAC; and 81.5%, 72.8%, and 83.0% in LATAM, respectively. Acinetobacter spp. susceptibility rates varied from 43.0% in E-EUR to 75.8% in LATAM (53.2% overall) for cefoperazone-sulbactam and from 19.8% in E-EUR to 40.2% in W-EUR (26.4% overall) for imipenem. Susceptibility rates varied widely among geographic regions and were generally lowest in E-EUR. Based on the potency and activity spectrum, cefoperazone-sulbactam remains among the most active compounds in vitro at published breakpoints. [ABSTRACT FROM AUTHOR]

Purpose: Factors influencing responsiveness to warfarin at treatment onset time were not well identified in Chinese patients undergoing heart valve replacement. We sought to select the most relevant factors that associated with patient response to warfarin early after heart valve surgery. Methods: In this observational study, 289 patients starting warfarin therapy early after heart valve replacement surgery were enrolled. CYP2C9 *1, *2, *3, and *5; VKORC1-1639 G>A, CYP4F2 V433M, and GGCX rs11676382 genotypes; clinical characteristics, response to therapy, and bleeding and thrombosis events were collected. The primary outcomes were the time to the first INR equal to or more than lower limit of therapeutic range and the warfarin dose requirements. Stepwise multiple linear regression was performed to develop a dosing algorithm to predict the warfarin dose requirements. Results: The results of univariate analysis showed lone VKORC1-1639 G>A, CYP2C9 *1/*3, cefazolin, cefoperazone-sulbactam, increased BMI, Δhemoglobin, and white blood cell count could significantly affect patient responsiveness to warfarin in the initial period of anticoagulation. Multivariate analysis resulted in an equation: Accumulated warfarin doses (mg) = 17.068 VKORC1-1639 G>A − 4.261 hypertension + 0.593 BMI − 0.115 age − 4.852 CYP2C9 *1/*3 − 2.617 cefazolin − 4.902 cefoperazone-sulbactam − 4.537, which could explain 40.2% of the variability in warfarin dose needed to reach the first INR equal to or more than lower limit of therapeutic range. Conclusions: Both genetic and clinical factors contributed to anticoagulation effect of warfarin in the initial period of treatment. Our findings could provide a basis for the personalized management of warfarin use in the early stage of anticoagulation in northern Chinese patients. [ABSTRACT FROM AUTHOR]

Background/Purpose: The aim of this study was to investigate the cefoperazone–sulbactam (CFP–SUL) susceptibilities of important Gram-negative bacteria (GNB) by agar dilution (reference method), disk diffusion, and two automated methods. Methods: A total of 799 GNB isolates, including Enterobacteriaceae (n = 500) and nonfermentative GNB (NFGNB, n = 299), were recovered from various clinical specimens collected at National Taiwan University Hospital, Taipei, Taiwan from November 2013 to December 2014. The agar dilution method, disk diffusion method, and two automated susceptibility systems (Phoenix and Vitek 2) were used for testing susceptibility of the isolates to CFP–SUL. Categories of susceptibility (susceptible, intermediate, or resistant) to CFP–SUL yielded from each method were interpreted according to CFP–SUL interpretive breakpoints proposed previously. The results of categorical agreement and errors obtained between the agar dilution method and the other three methods were analyzed. Results: The Vitek 2 system had the highest error rates against Escherichia coli (n = 150) and Enterobacter cloacae (n = 77) isolates, i.e., 6.7% and 11.7% minor errors, 8.5% and 1.7% major errors, and 40% and 20% very major errors, respectively. Additionally, the Vitek 2 system was also found to have a significantly lower sensitivity (44.4%) and lower positive predictive value (18.2%) for detecting CFP–SUL nonsusceptible E. coli isolates than other methods. For carbapenem-nonsusceptible Enterobacteriaceae isolates, the Vitek 2 system failed to detect correct susceptibility to CFP–SUL. The three methods failed to correctly detect CFP–SUL susceptibility categories against all NFGNB isolates except Pseudomonas aeruginosa. Conclusion: The Vitek 2 system is a suboptimal method in correctly detecting CFP–SUL susceptibility categories for E. coli, E. cloacae, and carbapenem-nonsusceptible Enterobacteriaceae isolates.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a rapidly emerging, life-threatening nosocomial infection. This study aimed to explore the risk factors, clinical features, antimicrobial therapy, and outcomes of CRAB bloodstream infections (BSIs).Methods: This is a retrospective, comparative analysis of data from patients with A. baumannii BSI, treated from 2012 to 2015 at a tertiary teaching hospital. Risk factors associated with CRAB BSI and factors associated with the 28-day mortality were evaluated using logistic analyses.Results: Data from 293 patients with confirmed A. baumannii BSI were included; 242 (82.6%) patients had CRAB BSI and 51 (17.4%) patients had non-CRAB BSI. Risk factors significantly associated with CRAB BSI were a previous intensive care unit (ICU) stay (P=0.029), cefoperazone–sulbactam use (P=0.030), and carbapenem use (P=0.004). Among 236 patients with A. baumannii BSI who were evaluable at 28 days after receiving antibacterial therapy, there were 86 deaths. Factors associated with the 28-day mortality were ICU stay after BSI (P=0.040), readmission within 90 days (P=0.029), Acute Physiology and Chronic Health Evaluation II (APACHE II) score at diagnosis >19 (P=0.012), tigecycline therapy (P=0.021), presence of septic shock (P=0.029), and multiple organ failure (P=0.016). Death rates in patients treated with tigecycline were 53.5% vs 24.1% in patients treated with other agents. Among 186 patients with CRAB BSI evaluable at 28 days, 84 patients died. The associated risk factors were an ICU stay after BSI (P=0.036), APACHE II score >19 at diagnosis (P=0.002), presence of septic shock (P=0.030), and multiple organ failure (P=0.007).Conclusion: This study demonstrated that an ICU stay and cefoperazone–sulbactam or carbapenem use were seen to be the risk factors associated with the development of CRAB BSI. Critical illness and tigecycline therapy were significantly associated with higher mortality of patients with A. baumannii BSI. [ABSTRACT FROM AUTHOR]

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Immunosuppressive patients are at risk of fungal and bacterial infections. Therefore, these patients receive prophylactic, preemptive, empirical or target antifungal and concomitant antibiotic therapy. To this end, caspofungin ( CAS) or voriconazole ( VRC) antifungals and cefoperazone-sulbactam ( CPZ/ SAM) or piperacillin-tazobactam ( PIP/ TAZ) antibiotics may be used. Here, we aimed to investigate the interaction between these antifungals and antibiotics by in vitro and in vivo methods. The interaction was tested by chequerboard analysis and fractional inhibitory concentration index ( FICI). It was also tested in a neutropenic mice-invasive candidiasis model and evaluated by fungal burden in kidney tissue of infected animals from the first day to the fifth day of treatment with 24 h intervals. A synergism was detected between CAS and CPZ/ SAM ( FICI = 0.1) and PIP/ TAZ ( FICI = 0.3). Fungal burden in tissues of drug-treated mice was reduced compared with controls in a time-dependent manner. In comparison with CAS-alone treated group, there were 1.32 log10 reductions of fungal burden in CAS + CPZ/ SAM (p = 0.002) and in CAS + PIP/ TAZ group (p = 0.14). The same interactions were not found with VRC and antibiotics. CPZ/ SAM had stronger synergistic interaction with CAS than PIP/ TAZ. The mechanism of synergism is not well understood. This is most likely due to an increase in the anticandidal effect of CAS plus antibiotics. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the effectiveness of piperacillin-tazobactam (PIP/TAZO) plus amikacin (AMK) (PIP/TAZO+AMK) versus cefoperazone-sulbactam (CS) plus AMK (CS+AMK) for the treatment of febrile neutropenia (FN) in children with cancer. The study was designed prospectively and randomized in 0- to 18-year-old children with lymphoma or solid tumor who were hospitalized with FN diagnosis. Consecutively randomized patients received either PIP/TAZO 360 mg/kg/day in 4 doses plus AMK 15 mg/kg/day in 3 doses or CS 100 mg/kg/day in 3 doses plus AMK 15 mg/kg/day in 3 doses intravenously. Treatment modification was defined as any change in the initial empirical antibiotic therapy. A total of 116 FN episodes were managed in 46 patients (26 boys and 20 girls) with a median age of 6.5 years (range .8-17.0) during the study period. Success rates without modification of therapy were 47.5% and 52.6% in PIP/TAZO+AMK group and CS+AMK group, respectively ( P >.05). No statistical difference was found between treatment groups in terms of durations of neutropenia, fever, and hospitalization. The overall success rate in all groups was 97.4%. No major side effect was observed in either group during the course of the study. Our study is the first to compare the effectiveness of PIP/TAZO+AMK and CS+AMK therapies. Both combinations were effective and safe as empirical therapy for febrile neutropenic patients. [ABSTRACT FROM AUTHOR]

Cefoperazone-sulbactam (SCF)-resistant Pseudomonas aeruginosa poses a big challenge in the use of SCF to treat infection caused by the pathogen. We have recently shown exogenous nitrite-enabled killing of naturally and artificially evolved Pseudomonas aeruginosa strains (AP-R CLIN-EVO and AP-R LAB-EVO , respectively) by SCF. However, the underlying mechanism is unknown. Here, reprogramming metabolomics was adopted to investigate how nitrite enhanced the SCF-mediated killing efficacy. Nitrite-reprogrammed metabolome displayed an activated pyruvate cycle (P cycle), which was confirmed by elevated activity of pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase. The activated P cycle provided NADH for the electron transport chain and thereby increased reactive oxygen species (ROS), which potentiated SCF to kill AP-R CLIN-EVO and AP-R LAB-EVO . The nitrite-enabled killing of AP-R CLIN-EVO and AP-R LAB-EVO by SCF was inhibited by PDH inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but promoted by ROS promoter Fe 3+ . SCF alone could not induce ROS, but SCF-mediated killing efficacy was enhanced by ROS. In addition, the present study demonstrated that nitrite repressed antioxidants, which were partly responsible for the elevated ROS. These results reveal a nitrite-reprogrammed metabolome mechanism by which AP-R CLIN-EVO and AP-R LAB-EVO sensitivity to SCF is elevated. IMPORTANCE Antibiotic-resistant Pseudomonas aeruginosa has become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. Understanding antibiotic resistance mechanisms and developing novel control measures are highly appreciated. We have recently shown that a reduced nitrite-dependent NO biosynthesis contributes to cefoperazone-sulbactam (SCF) resistance, which is reverted by exogenous nitrite, in both naturally and artificially evolved P. aeruginosa strains (AP-R CLIN-EVO and AP-R LAB-EVO , respectively). However, the mechanism is unknown. The present study reports that the nitrite-enabled killing of AP-R CLIN-EVO and AP-R LAB-EVO by SCF is attributed to the promoted production of reactive oxygen species (ROS). Nitrite activates the pyruvate cycle to generate NADH for the electron transport chain, which in turn promotes ROS generation. Nitrite-potentiated SCF-mediated killing is decreased by pyruvate dehydrogenase inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but increased by ROS promoter Fe 3+ . Furthermore, SCF-mediated killing is promoted by H 2 O 2 in a dose-dependent manner. In addition, the combination of nitrite and H 2 O 2 greatly enhances SCF-mediated killing. These results not only disclose a nitrite-ROS-potentiated SCF-mediated killing, but also show SCF-mediated killing is dependent upon ROS.

Objective of the present study was to describe the profile of infections in febrile neutropenia (FN) in acute leukemia and hematopoietic stem cell transplant (HSCT) with emphasis on response to therapy and outcome. In a prospective, observational single-institutional study, consecutive episodes of high-risk FN were enrolled over a 1½-year period. Uniform antibiotic policy and response criteria were used. Of the 200 episodes enrolled, acute leukemia induction comprised 40.5%, consolidation with high-dose cytarabine 22.5%, HSCT 29% (auto-HSCT 84%), and others 8% of the episodes, respectively. Microbiologically documented infections comprised 30% episodes, while bacteremia was documented in 26% episodes. Gram-negative isolates were more common (55.7%). Cefoperazone-sulbactam had the highest in vitro efficacy against Gram-negative rods. Carbapenem resistance was most prevalent among Acinetobacter spp. (80%) and Pseudomonas aeruginosa (50%). All Gram-positive cocci other than enterococci were susceptible to vancomycin, while 2/8 enterococci were resistant to it. Cefoperazone-sulbactam and amikacin were used as first-line antibiotics. Overall mortality was 8%. On multivariate analysis, mortality was associated with a nadir leukocyte count < 200/μl and an abnormal chest radiograph. Among high-risk FN patients, inspite of a high-level of resistance to antibiotics, a frontline regime containing cefoperazone-sulbactam could restrict the use of imipenem and resulted in an acceptable mortality of 8%. [ABSTRACT FROM AUTHOR]

Highlights • Cefoperazone-sulbactam and piperacillin-tazobactam have similar antimicrobial spectra. • Clinical efficacy and safety of the two antimicrobials for elderly patients with pneumonia remain uncertain. • In elderly patients with severe community-acquired pneumonia, cefoperazone-sulbactam and piperacillin-tazobactam had equal effectiveness and safety. • Similar effectiveness and safety profiles were observed between the two antimicrobials in elderly patients with hospital-acquired pneumonia/ventilator-associated pneumonia. • Cefoperazone-sulbactam and piperacillin-tazobactam are viable alternatives to each other for the treatment of elderly patients with pneumonia. Both cefoperazone-sulbactam (CFP-SUL) and piperacillin-tazobactam (PIP-TAZ) are β-lactam/β-lactamase inhibitor antibiotics and have a similar antimicrobial spectrum. However, comparative clinical efficacy and safety of CFP-SUL and PIP-TAZ for the treatment of pneumonia remain largely unknown, especially in elderly patients. Based on a multi-centre registry database, patients aged ≥65 years, diagnosed with severe community-acquired pneumonia (SCAP), hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), and given empirical therapy with CFP-SUL or PIP-TAZ were included in the analysis. The primary outcome of interest was the proportion of patients achieving clinical cure. Multi-variate logistic regression was conducted to compare odds ratios (OR) for the outcome between patients who received CFP-SUL and patients who received PIP-TAZ. In total, 941 elderly patients (624 with SCAP, and 317 with either HAP or VAP) were included in this study. Overall in-hospital mortality for the entire cohort was 19%. Clinical cure was achieved in 81% and 83% of patients with SCAP and HAP/VAP, respectively. Multi-variate logistic regression analysis showed similar odds for clinical cure for patients receiving CFP-SUL or PIP-TAZ among those with SCAP [adjusted OR 1.10, 95% confidence interval (CI) 0.71–1.70] or HAP/VAP (adjusted OR 0.72, 95% CI 0.30–1.76). Regarding safety, both CFP-SUL and PIP-TAZ were generally well tolerated with few reported adverse events. Among elderly patients with SCAP or HAP/VAP, empirical therapy with CFP-SUL is a viable alternative to PIP-TAZ, while considering antibiotic heterogeneity in the antimicrobial stewardship context. [ABSTRACT FROM AUTHOR]

Objective: This article presents the methodology and results of the pharmacoeconomic analysis of the Magnex Against Standard COmbination Therapy study comparing cefoperazone-sulbactam (Magnex) versus ceftazidime+ amikacin+metronidazole, in the treatment of intra-abdominal infections. Methods: This prospective, open label, phase IV study was conducted at 17 study sites in India and randomized subjects to receive either cefoperazone-sulbactam or the combination. Pharmacoeconomic analysis was included as a secondary objective and conducted in the clinical efficacy-evaluable (CEE) and the successfully treated patients. All comparisons between treatment groups were conducted using analysis of variance (ANOVA) or Wilcoxon Two-Sample tests. All costs were reported as Indian Rupee (INR) and actual unit costs collected in 2006 were used for the analyses [1 USD ∼ 40 INR; 1 Euro ∼ 56 INR]. Results: In the CEE and the successfully treated subset of patients, the average cost of treatment was numerically lower in the cefoperazone-sulbactam arm (not statistically significant). The analyses found that the cost-effectiveness ratio (CER) for cefoperazone-sulbactam was INR 17,640.53 and that for the comparator group was INR 22,075.16. Additionally, the incremental CER results showed that the cost of treatment was INR 21,505.59 lower per additional successfully treated patient in the cefoperazone-sulbactam group. Conclusions: The present study was the first of its kind to be conducted in the “price sensitive” Indian health-care setting. Though study was not powered for the difference in average cost of treatments, there was a trend favoring cefoperazone sulbactam. The findings from this study should encourage further conduct of similar analyses and increase the knowledge regarding pharmacoeconomics in India. [ABSTRACT FROM AUTHOR]

Cefoperazone-sulbactam (CS) and piperacillin-tazobactam (TZP) are used in the treatment of Gram-negative nosocomial infections (NIs). We aimed to compare the effects of these two antibiotics on mortality and treatment success. Patients treated with CS or TZP empirically for at least three days with suspicion of NI were included in this retrospective study. In total, 308 (154 patients in both treatment arms) patients were analyzed. Treatment success rate in CS and TZP group respectively (50% vs 51.2%, p  = 0.18), 28-day mortality rate (46.1% vs 42.8%, p  = 0.56) and antibiotic-related side effects (50.6% vs 46.1%, p  = 0.42) were similar except prolonged prothrombin time (19.4% vs 6.4%; p  = 0.001). According to this study results, CS and TZP have equal effectivity and safety for the empirical treatment of Gram-negative NIs. CS may be an appropriate alternative to TZP for antibiotic cycling or mixing strategy to reduce antibiotic resistance.

Objectives : Limited evidence has suggested that cefoperazone-sulbactam causes coagulation disorders and bleeding. Methods : The authors conducted a retrospective study to compare patients receiving cefoperazone-sulbactam versus those treated with cefoperazone-tazobactam or ceftazidime. Propensity-score matching was used to explore whether treatment with cefoperazone-sulbactam increased the risk of prothrombin time (PT) prolongation, coagulation disorders, and bleeding, or decreased platelets (PLT). Results : The cohort included 23,242 patients. Among patients receiving cefoperazone-sulbactam, the risk of PT prolongation, coagulation disorders, decreased PLT, and bleeding was 5.3%, 9.2%, 15.7%, and 4.2%, respectively. Propensity-score matching analyses suggested that cefoperazone-sulbactam increased the risk of PT prolongation (aOR 2.26, 95% CI 1.61-3.18), coagulation disorders (aOR 1.81, 95% CI 1.43-2.30), and decreased PLT (aOR 1.46, 95% CI 1.25-1.72), but not increase bleeding (aOR 1.05, 95% CI 0.79-1.40) compared with ceftazidime. Patients receiving cefoperazone-sulbactam had higher risk of PT prolongation (aOR 1.53, 95% CI 1.11-2.10), coagulation disorders (aOR 1.53, 95% CI 1.21-1.95), but not decreased PLT (aOR 0.93, 95% CI 0.81-1.07) or bleeding (aOR 1.11, 95% CI 0.87-1.42), compared with those receiving cefoperazone-tazobactam. Conclusion : Cefoperazone-sulbactam may be associated with a higher risk of PT prolongation and coagulation disorders compared with cefoperazone-tazobactam and ceftazidime.

Background and Objective: Macrolides are the recommended antibiotics for treating pertussis and preventing transmission. The causative bacterium, Bordetella pertussis, has high macrolide resistance and has recently circulated in China. The objective of this study was to find effective alternative antibiotics for treatment by assessing the in vitro activity and clinical efficacy of antibiotics against Bordetella pertussis., Methods: Bordetella pertussis was confirmed by agglutination with specific antisera and mass spectrometry. The MICs of antibiotics against isolates were determined using the Etest method. Treatment outcomes were clinically and microbiologically evaluated., Results: A total of 126 pertussis patients were diagnosed based on culture, 69.8% of whom were aged ≤6 months and 72.1% were treated with previous macrolides. Leucocytosis and lymphocytosis were observed in 29.4% and 54.8% of all patients, respectively. Both MIC 50 and MIC 90 of erythromycin, azithromycin, and clindamycin were >256mg/L, and 75.4% were highly macrolide resistant. The MIC 90 of trimethoprim-sulfamethoxazole, ampicillin, ampicillin-sulbactam, cefuroxime, ceftriaxone and cefoperazone-sulbactam were 0.38mg/L, 0.25mg/L, 0.19mg/L, 12mg/L, 0.19mg/L and 0.047mg/L, respectively. The MICs of piperacillin in all of the isolations were <0.016mg/L. Of the patients treated with single cefoperazone-sulbactam or piperacillin-tazobactam, 30 of 32 (93.8%) had significantly improved clinical symptoms and 24 of 25 (96%) had negative culture results after 2 weeks of therapy., Conclusion: Macrolide resistance in Bordetella pertussis is a serious problem in Zhejiang Province, China. Piperacillin/piperacillin-tazobactam and cefoperazone-sulbactam have potent antibacterial activity in vitro and in vivo, and may become the alternative choice for treating pertussis caused by macrolide-resistant isolates., (Copyright © 2019 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Cefoperazone, a third-generation cephamycin with broad-spectrum antibacterial activity and the ability to permeate bacterial cell membranes, is active against commonly encountered multidrug-resistant pathogens for hospital-acquired pneumonia (HAP) and health care-associated pneumonia (HCAP). To clarify the clinical effects of cefoperazone-sulbactam in the treatment of HAP and HCAP, we conducted an open-label, randomized, noninferiority trial that recruited patients aged ≥18 years suffering HAP/HCAP. Participants were randomly assigned to the cefoperazone-sulbactam (2 g of each per 12 h) or cefepime (2 g per 12 h) arm. Clinical and microbiological responses were evaluated at early posttherapy and test-of-cure visits. Recruited patients were allocated to subpopulations for intent-to-treat ( n  = 154), per-protocol ( n  = 147), and safety ( n  = 166) analyses. Intent-to-treat analysis demonstrated that (i) at the early posttherapy visit, 87.3% of patients receiving cefoperazone-sulbactam and 84.3% of patients receiving cefepime achieved clinical improvement or cure (risk difference of 3.0%; 95% confidence interval [CI], -9.0% to 15.0%), and (ii) at the test-of-cure visit, 73.1% of patients receiving cefoperazone-sulbactam and 56.8% of patients receiving cefepime were assessed as cured (risk difference of 16.3%; 95% CI, 0.0% to 33.0%). These results indicated the noninferiority of cefoperazone-sulbactam to cefepime, which was confirmed by per-protocol analysis. The chest radiographic consolidation/infiltration resolution rate, microbiological eradiation rate, and percentage of adverse events were comparable in both groups. Serious adverse events were rare, and none was judged to be related to the study drugs. Cefoperazone-sulbactam at 2 g every 12 h was noninferior to cefepime at 2 g every 2 h for patients with HCAP., (Copyright © 2019 American Society for Microbiology.)

Objectives: This study aims to assess the in vitro activity of cefoperazone alone and different cefoperazone-sulbactam ratios against different inoculum sizes of multidrug resistant organisms., Methods: Minimum inhibitory concentrations (MICs) of cefoperazone, cefoperazone-sulbactam at fixed ratio of 1:1 and 2:1 against a normal inoculum size of 5 × 10 5  CFU/ml and a high inoculum size of 5 × 10 7  CFU/ml were measured., Results: Each 33 isolates of extended-spectrum β-lactamases (ESBL)-producing Escherichia coli, ESBL-producing Klebsiella pneumoniae, carbapenem-resistant E. coli, and carbapenem-resistant Pseudomonas aeruginosa and a total of 122 isolates of carbapenem-resistant Acinetobacter baumannii were collected. After the addition of sulbactam at a 1:1 ratio, most MIC 50 and MIC 90 values decreased. Cefoperazone-sulbactam at a 1:1 ratio had a higher susceptibility rate against ESBL-producing E. coli, carbapenem-resistant E. coli, and carbapenem-resistant A. baumannii than cefoperazone-sulbactam at a 2:1 ratio (all P < 0.05). For ESBL-producing E. coli, the susceptibility rate of cefoperazone-sulbactam at ratios of (1:1) and (2:1) decreased from 97.0 to 87.9% and 90.9 to 60.6%, for normal to high inoculum, respectively. For ESBL-producing K. pneumoniae, both susceptibility rate of cefoperazone-sulbactam at ratios of (1:1) and (2:1) decreased from 75.8%, and 63.6% at normal inoculum to 51.5% and 42.4% at high inoculum., Conclusions: Cefoperazone-sulbactam at a 1:1 ratio has greater in vitro activity against most multidrug resistant organisms than cefoperazone-sulbactam at a 2:1 ratio. Such combinations were not influenced by the inoculum size of ESBL-producing E. coli and K. pneumoniae and could be a therapeutic option for treating severe infections., (Copyright © 2017. Published by Elsevier B.V.)

Background: Multidrug-resistant Acinetobacter baumannii (MDRAB) has emerged as an important pathogen of nosocomial infections. Even though cefoperazone-sulbactam is frequently used to treat MDRAB infections, this single-drug therapeutic approach often results in antibiotic resistance. Thus, combination therapy is preferred over single-drug therapy, particularly in the case of carbapenemase-producing gram negative bacteria. The aim of this study was to investigate the efficacy of cefoperazone-sulbactam combined with either tigecycline or rifampicin against clinical isolates of MDRAB., Methods: One hundred and three MDRAB bacteria were isolated from patients in two hospitals in China. The Epsilomer test (E test) was used to determine the minimum inhibitory concentration (MIC) values for amikacin, ceftazidime, cefepime, levofloxacin, rifampicin, cefoperazone-sulbactam, meropenem, tigecycline, and gentamicin against MDRAB isolates. In vitro effects of various antibiotic combinations were measured and the fractional inhibitory concentration index (FICI) was calculated for each drug combination., Results: Approximately 17.5% of the isolates were resistant to tigecycline, whereas more than 84.2% isolates were resistant to other antimicrobial agents tested in this study. Cefoperazone-sulbactam revealed remarkable synergistic effects when used in combination with either tigecycline or rifampicin. However, for the isolates with MICs lower than blood peak concentration after combination therapy, the ratio was lower in highly resistant isolates compared to the least resistant bacteria., Conclusions: In vitro cefoperazone-sulbactam in combination with tigecycline or rifampicin showed the highest synergistic or additive activity against MDRAB isolates. However, acquisition of highly antibiotic resistant bacteria may lessen the effectiveness of combination therapy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: To evaluate the reliability of using imipenem, meropenem, cefoperazone-sulbactam, piperacillin-tazobactam in the treatment of hospital-acquired Gram-negative bacterial infections with Monte Carlo simulation(MCS). Methods: The MIC of the four agents collected from hospital-acquired infections were detected in accordance with broth dilution method of Clinical and Laboratory Standard Institute (CLSI). MCS were conducted with MICs and the pharmacokinetics parameters of the four agents based on conventional dose regimens.The cumulative fraction of response (CFR) of time over MIC target attainment in different dosing regimen were generated. Results: A total of 2 541 strains, including 2 093 strains of Enterobacteriaceae and 448 strains of glucose non - fermentative bacilli were collected.The MIC(90) of imipenem and meropenem against Enterobacteriaceae were less than 1 mg/L in general, whereas MIC(90) of two agents with β-lactamase inhibitors was around 64 mg/L.As to glucose non - fermenting bacteria, MICs of all the four agents were very high, especially to Acinetobacter baumannii, which indicated MIC(50) more than 32 mg/L.MCS revealed that carbapenems had significantly higher CFR than those with β-lactamase inhibitors.Imipenem and meropenem (1 g, q8 h) obtained CFRs of 74.69% and 81.42%, respectively.The CFR of cefoperazone-sulbactam (2 g, q8 h) and piperacillin-tazobactam (4 g, q6 h) (both excluding β-lactamase inhibitors) were just 49.59% and 27.66% respectively, which increased after excluding A . baumannii in piperacillin-tazobactam. Conclusions: The conventional dose regimens of imipenem and meropenem are reliable for the empiric therapy of Gram-negative hospital-acquired bacterial infections.Piperacillin-tazobactam is suggested to use with higher doses or prolonged infusion time to satisfy the time of drug concentration exceeded the MIC(T>MIC)requirement.More clinical studies of cefoperazone-sulbactam should be conducted to optimize its regimen and guarantee its efficacy.

Background/purpose: The aim of this study was to investigate the cefoperazone-sulbactam (CFP-SUL) susceptibilities of important Gram-negative bacteria (GNB) by agar dilution (reference method), disk diffusion, and two automated methods., Methods: A total of 799 GNB isolates, including Enterobacteriaceae (n = 500) and nonfermentative GNB (NFGNB, n = 299), were recovered from various clinical specimens collected at National Taiwan University Hospital, Taipei, Taiwan from November 2013 to December 2014. The agar dilution method, disk diffusion method, and two automated susceptibility systems (Phoenix and Vitek 2) were used for testing susceptibility of the isolates to CFP-SUL. Categories of susceptibility (susceptible, intermediate, or resistant) to CFP-SUL yielded from each method were interpreted according to CFP-SUL interpretive breakpoints proposed previously. The results of categorical agreement and errors obtained between the agar dilution method and the other three methods were analyzed., Results: The Vitek 2 system had the highest error rates against Escherichia coli (n = 150) and Enterobacter cloacae (n = 77) isolates, i.e., 6.7% and 11.7% minor errors, 8.5% and 1.7% major errors, and 40% and 20% very major errors, respectively. Additionally, the Vitek 2 system was also found to have a significantly lower sensitivity (44.4%) and lower positive predictive value (18.2%) for detecting CFP-SUL nonsusceptible E. coli isolates than other methods. For carbapenem-nonsusceptible Enterobacteriaceae isolates, the Vitek 2 system failed to detect correct susceptibility to CFP-SUL. The three methods failed to correctly detect CFP-SUL susceptibility categories against all NFGNB isolates except Pseudomonas aeruginosa., Conclusion: The Vitek 2 system is a suboptimal method in correctly detecting CFP-SUL susceptibility categories for E. coli, E. cloacae, and carbapenem-nonsusceptible Enterobacteriaceae isolates., (Copyright © 2015. Published by Elsevier B.V.)