AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.
- MeSH
- antibakteriální látky škodlivé účinky farmakokinetika MeSH
- ceftazidim škodlivé účinky farmakokinetika MeSH
- chromatografie kapalinová MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- mikrobiální testy citlivosti MeSH
- nádory * komplikace farmakoterapie MeSH
- off-label použití léčivého přípravku MeSH
- pseudomonádové infekce * farmakoterapie MeSH
- Pseudomonas aeruginosa MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. METHODS: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7-15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. RESULTS: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.
- MeSH
- antibakteriální látky terapeutické užití MeSH
- azabicyklické sloučeniny aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- ceftazidim aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- dítě MeSH
- fixní kombinace léků MeSH
- kojenec MeSH
- kombinovaná farmakoterapie MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metronidazol aplikace a dávkování škodlivé účinky farmakokinetika terapeutické užití MeSH
- mikrobiální testy citlivosti MeSH
- mladiství MeSH
- mnohočetná bakteriální léková rezistence MeSH
- nitrobřišní infekce diagnóza farmakoterapie mikrobiologie MeSH
- pooperační komplikace * MeSH
- předškolní dítě MeSH
- věkové faktory MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: When combined with ceftazidime, the novel non-β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). METHODS: The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%. RESULTS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. CLINICAL TRIALS REGISTRATION: NCT01499290 and NCT01500239.
- MeSH
- antibakteriální látky * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- azabicyklické sloučeniny * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- ceftazidim * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- metronidazol * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nitrobřišní infekce farmakoterapie epidemiologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thienamyciny * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
The bla(PER-1) presence was sought by PCR in 289 ceftazidime resistant Gram-negative bacteria isolated at Dokuz Eylul University Hospital (Turkey) between 1998 and 2003. PER-1 production rates were 32.3, 33.9, 14.9 and 37.9% in the 1998-2000 period, 2001, 2002 and 2003, respectively. bla(PER-1) was detected in 46.2 and 35.9% of ceftazidime-resistant Pseudomonas aeruginosa and Acinetobacter baumannii isolates, respectively. ERIC-PCR results revealed that dissemination of two endemic clones for both P. aeruginosa (X and Y) and A. baumannii (A and B) was responsible for the high prevalence. Results of the conjugation tests and plasmid curing experiments suggested that bla(PER-1) was located on the chromosome in the representative strains. It was also shown for the first time that bla(PER-1) in a clinical isolate was associated with class-1 integron which could facilitate dissemination of bla(PER-1) among bacteria.
- MeSH
- Acinetobacter baumannii genetika imunologie izolace a purifikace MeSH
- beta-laktamasy genetika imunologie izolace a purifikace MeSH
- beta-laktamová rezistence genetika imunologie účinky léků MeSH
- ceftazidim imunologie škodlivé účinky terapeutické užití MeSH
- DNA fingerprinting metody využití MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- polymerázová řetězová reakce metody využití MeSH
- Pseudomonas aeruginosa genetika imunologie izolace a purifikace MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Turecko MeSH
- MeSH
- ceftazidim aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- dítě MeSH
- fixní kombinace léků MeSH
- infekce spojené se zdravotní péčí farmakoterapie mikrobiologie prevence a kontrola MeSH
- infekce farmakoterapie komplikace mikrobiologie MeSH
- intenzivní péče o novorozence ošetřování trendy MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
