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This single-center study evaluated the efficacy and safety of tazobactam/ceftolozane (TAZ/CTLZ) in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice. This study included 50 patients, including 35 with intraabdominal abscess or peritonitis, 5 with liver abscess, 4 with cholecystitis, and 6 with cholangitis with sepsis. Of the 50 patients, 29 received TAZ/CTLZ and metronidazole after a prior antibacterial therapy failure, including tazobactam/piperacillin, cefmetazole, and levofloxacin. Source control was performed in 36 patients. The clinical response could be evaluated in 49 patients. The clinical cure rate at end-of-therapy was 91.8% (45 of 49 patients) and that at test-of-cure was 89.6% (43 of 48 patients). Of 5 patients in whom clinical response at test-of-cure was a failure, 1 developed infectious disease during chemoradiotherapy for recurrent cancer and 4 after liver resection or pancreatoduodenectomy. Three of the 4 patients were associated with pancreatic juice leakage. Isolated pathogens were eradicated or presumably eradicated in 27 of 31 (87.1%) patients in whom microbiological response at test-of-cure could be evaluated. The response rate for AmpC-producing Enterobacteriaceae was 87.5%. Nausea was observed in two patients. Aspartate and alanine aminotransferase activities were increased in 3 of the 50 (6.0%) patients. The activities improved after the antibiotic discontinuation. This observational study demonstrated that TAZ/CTLZ in combination with metronidazole has a favorable effect without major drug-related adverse events for intraabdominal infection in the hepato-biliary-pancreatic field in clinical practice although the efficacy of TAZ/CTLZ may decrease in compromised patients. [ABSTRACT FROM AUTHOR]

• Phase III study of ceftolozane/tazobactam (C/T) plus metronidazole for complicated intra-abdominal infection in China. • C/T plus metronidazole was noninferior to meropenem for clinical response. • Safety was comparable between C/T plus metronidazole and meropenem groups. • C/T plus metronidazole had efficacy against extended-spectrum β-lactamase-positive Enterobacterales. This study aimed to evaluate the efficacy and safety of ceftolozane/tazobactam (C/T) plus metronidazole versus meropenem plus placebo for the treatment of complicated intra-abdominal infection (cIAI) in Chinese adult participants. In this phase III clinical trial (NCT03830333), Chinese adult participants with cIAI were randomized 1:1 to receive C/T plus metronidazole or meropenem plus placebo. The primary objective was to assess C/T plus metronidazole for noninferiority versus meropenem for clinical response rate at the test of cure (TOC; 28 ± 2 days after study start) visit in the clinically evaluable population. Secondary endpoints included clinical and microbiologic responses at the TOC and end-of-treatment (≤24 hours after last dose) visits and adverse event rates. Clinical cure at the TOC visit in the clinically evaluable population was 95.2% and 93.1% for C/T plus metronidazole and meropenem, respectively (between-treatment difference: 2.1% [95% confidence interval: -4.7%, 8.8%]); thus, noninferiority was met. Clinical responses at the TOC and end-of-treatment visits and microbiologic responses at the TOC visit were consistent with the primary efficacy endpoint. Safety was comparable between study treatment groups. In Chinese adult participants with cIAI, C/T plus metronidazole was noninferior to meropenem, with comparable safety. [ABSTRACT FROM AUTHOR]

• High-dose cefepime-tazobactam is under clinical development • A total of 23,246 organisms from 133 medical centers in 34 countries were tested • Cefepime-tazobactam inhibited 97.6% of Enterobacterales at ≤8 mg/L • Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem • Cefepime-tazobactam inhibited 96.2% of P. aeruginosa at ≤8 mg/L High-dose cefepime-tazobactam (WCK 4282) is currently under clinical development at a dosage of 2 grams/2 grams every 8 hours with prolonged infusion (90 minutes). To evaluate the in vitro activity of high-dose cefepime-tazobactam. A total of 23, 246 gram-negative organisms were collected from 133 medical centers (34 countries) in 2018-2019 and susceptibility was tested by broth microdilution method against cefepime-tazobactam (tazobactam at fixed 8 mg/L) and comparator agents. Cefepime-tazobactam and cefepime inhibited 97.6% and 85.4% of Enterobacterales isolates (n = 18,143) at ≤8 mg/L, respectively. Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem (97.0% susceptible) and greater than ertapenem (95.2% susceptible) or piperacillin-tazobactam (88.0% susceptible). Moreover, cefepime-tazobactam retained potent activity against meropenem-susceptible Enterobacterales isolates that were nonsusceptible to ceftazidime, ceftriaxone, and piperacillin-tazobactam (96.3% inhibited at ≤8 mg/L) or ceftolozane-tazobactam (96.2% inhibited at ≤8 mg/L). Against P. aeruginosa (n = 4,553), the percentage of isolates inhibited at ≤8 mg/L of cefepime-tazobactam (82.7%) was higher than meropenem (76.0%) or piperacillin-tazobactam (76.4%), and the percentage inhibited at the proposed pharmacokinetic/pharmacodynamic breakpoint of ≤16 mg/L (92.2%) was comparable with ceftolozane-tazobactam (93.5%). The results of this in vitro study support the clinical development of cefepime-tazobactam as a carbapenem-sparing option to treat infections caused by Enterobacterales and P. aeruginosa, including multidrug-resistant isolates. [ABSTRACT FROM AUTHOR]

We describe a case of a 48 years old male with left sided endocarditis and septic emboli secondary to a Pseudomonas aeruginosa strain that developed resistance to other β-lactam antibiotics during therapy resulting in prolonged bacteremia. Blood cultures sterilized within 1 day of initiating ceftolozane/tazobactam 3 g every 8 hours in combination with ciprofloxacin. Steady state free ceftolozane plasma Cmax and Cmin concentrations were calculated to be 122.2μg/mL and 24.3μg/mL, respectively. The multidrug-resistant strain harbored chromosomal β-lactamases OXA-486 and PDC-3, mutations in ampD and dacB predicted to lead to ampC over-expression, and mutations in OprD predicted to decrease outer membrane permeability. Following completion of a 42 day course and aortic valve replacement, the patient was deemed clinically cured without recurrence of infection at follow up 2 years later. To our knowledge, this is the first reported case to measure ceftolozane concentrations during the treatment of endocarditis which supports dose optimization approaches of severe endovascular disease due to multidrug resistant pathogens. [ABSTRACT FROM AUTHOR]

• The unusually high daily dosage of ceftolozane posts great challenge in the impurity control. • During the final process development, A dimeric impurity, 2, was consistently observed at near the threshold reporting level in the ceftolozane API. • A method was developed to enrich and isolate dimeric impurity 2 for subsequent analysis. • The unique structure of 2 was established through LC/HRMS, HRMSMS and 2D-NMR studies for the first time. • A kinetic study of the formation of 2 was conducted to determine the best conditions to control 2 in the final chemical process. Ceftolozane is MSD's 5th generation cephalosporin antibiotic with broad-spectrum gram-negative activity. While refining the synthetic route to the drug substance, a dimeric impurity was observed in the final active pharmaceutical ingredient (API) of ceftolozane. Through impurity enrichment and preparative isolation, the structure of the impurity was subsequently established through LC/HRMS, HRMSMS, H/D exchange and 2D-NMR studies. A kinetic study of the impurity formation was conducted to determine the best conditions to control it in the final chemical process. [ABSTRACT FROM AUTHOR]

Abstract Tazobactam/ceftolozane is a combination of a β-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage. Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 μg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 μg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population. The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients. [ABSTRACT FROM AUTHOR]

Abstract Tazobactam/ceftolozane, a novel antimicrobial therapy, is active against Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. We report the results of the efficacy and safety of tazobactam/ceftolozane in Japanese patients with complicated intra-abdominal infections (cIAI). A multicenter, open-label, noncomparative study (MK-7625A Protocol 013, ClinicalTrials.gov Identifier: NCT02739997) to investigate the efficacy and safety of tazobactam/ceftolozane used in combination with metronidazole in Japanese patients with cIAI was conducted. One hundred Japanese patients with cIAI received tazobactam/ceftolozane 1.5 g (tazobactam 0.5 g/ceftolozane 1 g) plus metronidazole 500 mg intravenously every 8 h for 60 min for 4–14 days. The clinical response rate at the Test-of-Cure visit (TOC; Day 28 ± 2 days) was 92.0% (81/88 subjects). By disease type, the clinical response rates were 92.3% (24/26) for cholecystitis, 100% (6/6) for liver abscess, 93.5% (58/62) for intra-abdominal abscess and 90.2% (55/61) for peritonitis. The per-subject microbiological response rate at the TOC was 90.2% (55/61). Per-pathogen microbiological response rates in the most common baseline pathogens were Escherichia coli 90.2% (37/41), Kebsiella pneumoniae 91.7% (11/12), Streptococcus anginosus 100% (11/11), Streptococcus constellatus 90.0% (9/10) and Bacteroides fragilis 95.2% (20/21). The most common drug-related AEs were aspartate aminotransferase increased (11.0%) and alanine aminotransferase increased (9.0%). No serious drug-related AE was reported during the study. The favorable effect of tazobactam/ceftolozane in the treatment of cIAI suggests that the agent will be useful in clinical practice in Japan. [ABSTRACT FROM AUTHOR]

Abstract We report efficacy and safety results for a combination of a novel cephalosporin class antibiotic and a β-Lactamase inhibitor, tazobactam/ceftolozane (1:2) at a dose of 1.5 g intravenously every 8 h in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection. This study design was a nonrandomized, multicenter, open-label trial, and the treatment period was 7 days. Of 115 patients enrolled in this study, 114 received tazobactam/ceftolozane, and 90 were included in the efficacy analyses. Ninety-nine isolates (bacterial count ≥105 CFU/mL) were identified by urine culture. The main baseline uropathogens were Escherichia coli (80 isolates), Klebsiella pneumoniae (8 isolates), and Proteus mirabilis (3 isolates). Of these, 13 isolates were ESBL-producers. The favorable per-patient microbiological response rate at 7 days after the final administration of tazobactam/ceftolozane was 80.7% (71/88). The response rate in uncomplicated pyelonephritis was 90.0% (36/40), complicated pyelonephritis 63.6% (14/22), and complicated cystitis 80.8% (21/26). The favorable clinical response rate was 96.6% (86/89), and composite response rate (based on microbiological and clinical response) was 80.7% (71/88). The eradication rate by uropathogen was 83.5% (66/79) in E. coli , 42.9% (3/7) in K. pneumoniae , and 100% (3/3) in P. mirabilis. The incidence of drug-related adverse events was 17.5% (20/114 patients). The most common drug-related adverse events were diarrhea and alanine aminotransferase increased in 5.3% (6/114 patients each). Drug-related serious adverse events and deaths were not observed. These results support the safety and efficacy of tazobactam/ceftolozane and suggest it will be a useful treatment for uncomplicated pyelonephritis and complicated urinary tract infection. [ABSTRACT FROM AUTHOR]

Abstract Background Ceftolozane, in combination with the β-lactamase inhibitor tazobactam, is a new option in the pipeline against multidrug-resistant Gram-negative bacilli. As for other β-lactam antibiotics, optimizing the use of ceftolozane-tazobactam is advisable, especially in difficult-to-treat infections. In this regard, therapeutic drug monitoring would be required to guide the treatment of ceftolozane-tazobactam. Thus, we aimed to develop and validate procedures based on UHPLC-MS/MS for measurement of ceftolozane and tazobactam plasma concentrations in clinical practice. Material and methods Analyses were conducted using an Acquity® UPLC® integrated system coupled to an Acquity® TQD® tandem-quadrupole mass spectrometer. Ceftolozane, tazobactam and their internal standards (ceftazidime-D 5 and sulbactam) were detected by electrospray ionization mass spectrometry in positive and negative ion multiple reaction monitoring modes, using transitions of 667.2 → 199.3/139.0 and 551.9 → 467.9 for ceftolozane and ceftazidime-D 5 , and 299.0 → 138/254.9 and 232.0 → 140.0 for tazobactam and sulbactam. Measurement procedures developed were used for guiding the treatment and adjusting daily dose of ceftolozane-tazobactam in patients with osteoarticular infections. Results Coefficients of variation and absolute relative biases were <7.9% and 6.5% in all cases. The lower limit of quantification, linearity, normalized-recoveries, normalized-matrix effects and measurement uncertainties for ceftolozane were: 0.97 mg/L, (0.97–125) mg/L, ≤113.6%, ≤108.7%, and ≤ 18.7%, respectively; and for tazobactam: 1.04 mg/L, (1.04–125) mg/L, ≤103.6%, ≤101.9%, and ≤ 20.0%. No interferences and carry-over were observed. Patients plasma concentrations were higher than the recommended 3–4 times the minimal inhibitory concentrations. Conclusions Our measurement procedures are suitable for therapeutic drug monitoring of ceftolozane-tazobactam in patients with osteoarticular infections. Highlights • UHPLC-MS/MS procedures for measurement of ceftolozane-tazobactam concentration were developed. • Measurement procedures were validated using the EMA and CLSI validation guidelines. • Verification of the applicability of the procedures were performed using patient samples. • The measurement procedures can be useful for therapeutic drug monitoring of ceftolozane-tazobactam. • The measurement procedures developed are well suited to routine hospital practice. [ABSTRACT FROM AUTHOR]

• Antibacterial resistance has led to a need for multiple treatment options • Ceftolozane/tazobactam (C/T) was well tolerated in healthy Chinese participants • C/T pharmacokinetics (PK) for Chinese participants was comparable to that in other ethnicities • PK in Chinese participants supports C/T dosing schedule used by other ethnicities Ceftolozane/tazobactam (C/T) is approved in several countries to treat complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. There is a paucity of pharmacokinetics and safety data for C/T in Chinese participants. This study evaluated the pharmacokinetics, safety, and tolerability of C/T in 12 healthy Chinese participants after three single administrations of increasing doses (0.75 g, 1.5 g, and 3 g) and multiple administrations of 1.5 g C/T every 8 h for 3 days. After single doses, maximum concentrations of ceftolozane and tazobactam were reached by the end of the 1-h infusion and declined in a biphasic manner thereafter, with mean half-lives of 1.9–2.2 h and 0.74–0.95 h, respectively. Volume of distribution (V d) and renal clearance (CL) were consistent across the three single-dose levels for ceftolozane (V d , 15.8–19.5 L; CL, 5.68–6.09 L/h) and tazobactam (V d , 23.3–28.6 L; CL, 20.8–23.5 L/h). Area under the concentration–time curve (AUC) extrapolated to infinity (ceftolozane, 88.1–328 h∙μg/mL; tazobactam, 10.7–48.0 h∙μg/mL) increased in a dose-dependent manner. After multiple doses over 3 days, AUC from time 0 to 8 h, and concentration at the end of infusion were similar to single-dose measurements (geometric mean ratios, 0.87–1.01 for both drugs). C/T was well tolerated, with no serious adverse events or discontinuations reported; all adverse events were mild. The pharmacokinetics and safety/tolerability of C/T in healthy Chinese participants was comparable to that in previous studies in other populations, supporting the use of C/T for the treatment of Chinese patients. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa causes a variety of life-threatening infections, some of which are associated with planktonic and others with biofilm states. Herein, we tested the combination of the novel cephalosporin, ceftolozane, with the β-lactamase inhibitor, tazobactam, against planktonic and biofilm forms of 54 clinical isolates of P. aeruginosa , using cefepime as a comparator. MIC values were determined following Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum biofilm inhibitory concentration (MBIC) values were determined using biofilm-laden pegged lids incubated in antimicrobial challenge plates containing varying concentrations of ceftolozane/tazobactam. Pegged lids were then incubated in growth recovery plates containing cation-adjusted Mueller–Hinton broth to determine the minimum biofilm bactericidal concentration (MBBC). Ceftolozane/tazobactam was highly active against planktonic P. aeruginosa , with all 54 isolates studied testing susceptible (MIC ≤4/4 μg/mL). On the other hand, 51/54 biofilm P. aeruginosa had MBICs ≥16/4 μg/mL, and all 54 isolates had MBBCs >32 μg/mL. Of the 54 isolates, 45 (83.3%) tested susceptible to cefepime, with the MIC 50 /MIC 90 being 4/16 μg/mL, respectively, and the MBIC 90 and MBBC 90 both being >256 μg/mL. Although ceftolozane/tazobactam is a promising antimicrobial agent for the treatment of P. aeruginosa infections, it is not highly active against P. aeruginosa biofilms. [ABSTRACT FROM AUTHOR]

The continuing increase in multidrug-resistant organisms (MDROs) worldwide has created new challenges in treating complicated intra-abdominal infections (cIAIs). A number of novel antimicrobial agents have been developed against resistant pathogens. To target extended-spectrum β-lactamase (ESBL)-producing pathogens, novel β-lactam antibiotics, such as ceftolozane/tazobactam, ceftazidime/avibactam, aztreonam/avibactam, imipenem/relebactam and S-649266, are antimicrobial alternatives for cIAIs. Two new drugs, eravacycline and plazomicin, have activity against Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae , carbapenem-resistant Acinetobacter baumannii and ESBL-producers. New lipoglycopeptides and oxazolidinones provide feasible options against resistant Gram-positive pathogens. These novel antimicrobials may play a role in improving the clinical outcomes of cIAIs caused by MDROs. [ABSTRACT FROM AUTHOR]

• First LC-MS/MS method to simultaneously analyze ceftolozane and tazobactam. • Most sensitive ceftolozane and tazobactam LC-MS/MS method. • The method is rapid with a simple extraction procedure. • The method was validated per US FDA regulatory guidelines. The purpose of this work was to develop and validate a single sensitive, selective and rapid bioanalytical method to determine ceftolozane and tazobactam concentrations in human plasma and urine and to use this method to analyze samples from a human clinical study. Human plasma and urine samples were prepared by protein precipitation using a solution of acetonitrile, water and formic acid. Following protein precipitation, samples were analyzed by liquid chromatography tandem mass spectrometry. Chromatographic resolution was achieved on a Kinetex PFP column using a gradient elution, a flow rate of 0.4 mL/min, and a total run time of 5 min. Positive electrospray ionization was employed and analytes were quantitated using multi-reaction monitoring mode. Method validation was conducted in accordance with Unites States Food and Drug Administration's regulatory guidelines for bioanalytical method validation. Calibration curves were determined to linear over the range of 0.1 to 40 µg/mL for ceftolozane and 0.05 to 20 µg/mL for tazobactam. The method was determined to be accurate (−6.24 to 12.53 percent relative error), precise (less than 13.28 percent standard deviation) and sensitive in both human plasma and urine. Ceftolozane and tazobactam were determined to be stable across a battery of stability studies including autosampler, benchtop, freeze/thaw and long-term stability. This validated method successfully applied to human clinical samples to determine the concentration versus time profiles of the intravenously administered combination of Zerbaxa (ceftolozane-tazobactam) in burn patients. [ABSTRACT FROM AUTHOR]

Although multiple antimicrobial resistance (AMR) determinants can confer the same in vitro antimicrobial susceptibility testing (AST) phenotype, their differing effect on optimal therapeutic choices is uncertain. Using a large population-based collection of clinical strains spanning a 3.5-year period, we applied WGS to detect inhibitor resistant (IR), extended-spectrum β-lactamase (ESBL), and carbapenem resistant (CR) β-lactamase (bla) genes and compared the genotype to the AST phenotype in select isolates. All bla NDM-1 (9/9) and the majority of bla NDM-1/OXA-48 (3/4) containing isolates were resistant to CAZ/AVI as predicted by WGS. The combination of ATM and CAZ/AVI restored susceptibility by disk diffusion assay. Unexpectedly, clinical Kp isolates bearing bla KPC-8 (V240G) and bla KPC-14 (G242 and T243 deletion) did not test fully resistant to CAZ/AVI. Lastly, despite the complexity of the β-lactamase background, CAZ/AVI retained potency. Presumed phenotypes conferred by AMR determinants need to be tested if therapeutic decisions are being guided by their presence or absence. [ABSTRACT FROM AUTHOR]

Ceftolozane is a newer β-lactam antibiotic drug effective against gram-negative pathogens. Its pharmacokinetic parameters are dominated by the patients' kidney function. Consequently, in patients with impaired kidney function or those who are treated with different forms of renal replacement therapy, therapeutic drug monitoring (TDM) of ceftolozane is strongly recommended to enhance safety and efficiency of the antibiotic treatment. Various methods for the quantification of ceftolozane in plasma samples have been described utilizing HPLC-UV or LC-MS/MS. However, all these methods are impaired by the instability of ceftolozane in plasma samples. In this work, we have determined the stability of ceftolozane in human plasma at temperatures of 40 °C, 23 °C, 6 °C and − 20 °C. At 6 °C and − 20 °C, ceftolozane was stable in human plasma over the observed time range of 7 days. At 23 °C and 40 °C, plasma samples were of acceptable (i.e. less than 15% decay) stability over time ranges of 71.2 h and 5.6 h, requiring expedited sample transport to the laboratory. Dried blood spots (DBS) were reported in the literature as matrix with beneficial properties regarding stabilities of β-lactam antibiotics. However, in this study we found that ceftolozane was of inferior stability in this matrix in comparison to plasma. Thus, DBS cannot be recommended as matrix for ceftolozane in TDM. [ABSTRACT FROM AUTHOR]

We report the successful use of ceftolozane/tazobactam (C/T) to treat a pulmonary exacerbation in a 35 year old female, post lung transplant, with cystic fibrosis (CF), malnutrition, chronic kidney disease, and multi-drug resistant Pseudomonas aeruginosa infection (MDR PSA). Given the complexity of the clinical profile, we measured drug levels of C/T during treatment of her current exacerbation to determine pharmacokinetics. The patient achieved an estimated ceftolozane peak of 174.1 μg/mL and trough of 9.2 μg/mL. Serum half-life was found to be slightly shorter than previously reported in normal subjects, (2.3 hr. vs. 2.6 hr.) despite the presence of renal insufficiency. Treatment resulted in improvement in serum inflammatory markers and symptoms and was well-tolerated. [ABSTRACT FROM AUTHOR]