Ceftolozane-tazobactam pharmacokinetics during extracorporeal membrane oxygenation in a lung transplant recipient

Abstract

22Ceftolozane-tazobactam pharmacokinetics during extracorporeal membrane oxygenation (ECMO) 23 has not been previously studied. In this work we report on the ceftolozane and tazobactam 24 plasmatic levels in a lung transplant recipient during ECMO, treated with ceftolozane-tazobactam 25 (2g/1g, intravenously every 8 h, 1 h infusion) for a Pseudomonas aeruginosa pulmonary infection. 26Ceftolozane Cmax and Cmin, monitored during 96 hrs, remained above 60 and 20 µg/mL, 27 respectively, with optimal drug exposure (100% %T MIC ). Tazobactam levels were above 1.9 µg/mL. 28 29 30patient had a normal renal function with creatinine clearance, estimated using the Cockcroft-Gault 83 formula, above 90 mg/min (range 90-150 mg/min) ( Figure 1). 84Ceftolozane and tazobactam plasma concentrations were monitored for 96 h following the first 85 administration. Plasma samples were obtained ½ h after the end of each ceftolozane-tazobactam 86 infusion and immediately before the beginning of the following dose (Cmax and Cmin 87 respectively). The samples were centrifuged at 1,600 g for 10 min to yield at least 1 ml of plasma. 88 Plasma samples were stored at −80°C until the assay. Ceftolozane and tazobactam concentrations 89 were quantified using a validated HPLC method at the Chemotherapy Laboratory of the Department 90 of Health Sciences (University of Florence, Italy). (11) 91In the following days the patient clinical conditions improved and, on day 3 after the lung 92 transplant, the vaECMO was switched again to vvECMO. 93In the 96 h of drug monitoring, the ceftolozane levels remained constantly above the isolate MIC. In 94 the first 48 h, ceftolozane Cmax were persistently above 100 µg/mL. Later, from 48 to 96 h, there 95 was a decline in Cmax and Cmin, which, however, remained above 60 and 20 µg/mL, respectively 96 ( Figure 1). Tazobactam concentration were above 1.9 µg/mL for all the monitored period. 97ECMO was halted on day 8 after lung transplantation. The patient's conditions eventually improved 98 and, on day 15 after lung transplantation, the antimicrobial therapy was discontinued. No adverse 99 events were attributed to the ceftolozane-tazobactam administration. Four consecutive tracheal 100 aspirate cultural exams, performed in the last day of treatment and 3, 4, and 7 days after the 101 antibiotics discontinuation, did not grow P. aeruginosa or any other pathogen. 102Concluding, we documenting the success of ceftolozane-tazobactam treatment for a case of 103 carbapenem-resistant P. aeruginosa LRTI in a lung transplant recipient subjected to ECMO 104 support. TDM revealed that optimal drug exposure was achieved, with a ceftolozane concentration 105 at 100% %T MIC . Of note, in this case, optimal Cmax and Cmin were obtained using a 3 g 106 cefotolozane-tazobactam dose every 8 h, using a standard 1 h infusion time. During the TDM 107 period we assisted to a decrease of ceftolozane/tazobactam Cmin and Cmax that could be attributed 108 6 to the increase in the patient's creatinine clearance values. In fact, it was previo...

Systematic Literature Review of Real-World Evidence of C Eftolozane/Tazobactam for the Treatment of Respiratory Infections

“…44 Twelve studies reported 74 patients that were immunocompromised. 17,20,[25][26][27][28][29]39,40,42,43,45 Of these studies, two included only immunocompromised patients. 28,43 As with ICU patients, this is likely an underestimation as most multi-infection studies did not provide a breakdown by infection type.…”

“…Thirty-two studies, comprising 650 patients (98.8% of patients), reported a causative pathogen. [15][16][17][18]47 The most prevalent causative pathogen reported was P. aeruginosa (92.8%; N = 603 patients; 31 studies), of which 11.9% (N = 72) were caused by non-resistant P. aeruginosa, or the resistance level was not speci ed, 0.5% (N = 3) were caused by carbapenemresistant (CR) P. aeruginosa, 73.3% (N = 442) were caused by MDR P. aeruginosa, 13.8% (N = 83) were caused by extensivelydrug-resistant (XDR) P. aeruginosa, and 0.5% (N = 3) were caused by pandrug-resistant (PDR) P. aeruginosa. In the other study that reported a causative pathogen, all patients (N = 47) had an extended-spectrum β-lactamase (ESBL)-positive Enterobacterales infection.…”

“…28 In this study, patients were immunocompromised, each of whom had hematologic malignancies or were hematopoietic-cell transplant recipients, and were infected by MDR P. aeruginosa. 28 Moreover, three single-patient case reports reported C/T durations exceeding the maximum label dose; 17,34,39 with two studies reporting a 42-day duration. 34,39 In these two studies, C/T was used for a recurrent CR P. aeruginosa infection in a patient admitted to the ICU, 39 and as desensitization therapy for a patient with VABP.…”

“…Every included study reported outcomes for respiratory patients: 29 reported clinical outcomes, 15-25,27−30,32-34,36−46 13 reported microbiological outcomes, 15-17, 24,25,29, 32-35,38,42, 44 and 26 reported mortality outcomes. [15][16][17]20,21,[24][25][26][27][28][29][31][32][33][34][36][37][38][39][40][41][42][43][44][45]47 Excluding single patient case reports, 17 studies (including 494 patients) reported clinical success rates of 51.4 22 -100.0%, 16,25,30,44,46 with 10 studies (55.6%) reporting success rates of > 70%. 16,18,19,23,25,30,42,44−46 In larger studies (> 30 patients; seven studies), 18,19,22,24,36,43,45 clinical success rates ranged from 51.4 22 -78.3%.…”

Real-world Use of Ceftolozane/tazobactam: a Systematic Literature Review

“…Including studies that recruited patients from multiple countries, the most common study locations were the US (N = 50), (21, 22, 24, 27-29, 33, 34, 39-41, 43-45, 50, 51, 54, 56, 57, 59, 61, 62, 68-71, 73-77, 79-85, 87-92, 94, 95, 97-100) Spain (N = 15), (26, 28, 30-32, 35-37, 42, 47, 49, 58, 66, 79, 96) and Italy (N = 13). (18,20,23,25,48,52,53,55,64,67,72,79,86) A variety of study designs were captured: 27 were non-comparative retrospective studies, (18,19,22,24,25,28,32,33,40,41,79,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(94)(95)(96)(97)(98)(99) 14 were case series, (20, 21, 29, 31, 34-39, 42, 43, 82, 100) ve were comparative (including two cohort studies, (80,83) and three case-control studies, (23,…”