-
Antimicrobial Agents and Chemotherapy Jun 2022The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized...
The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized dosing regimens. Total and unbound ceftriaxone concentrations were obtained from two pharmacokinetic studies and from a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit. Population pharmacokinetic analysis and Monte Carlo simulations were used to assess the probability of achieving a free trough concentration/MIC ratio of ≥1 using Pmetrics for R. A total of 474 samples (267 total and 207 unbound) were available from 36 patients. A two-compartment model describing ceftriaxone-albumin binding with both nonrenal and renal elimination incorporating creatinine clearance to explain the between-patient variability best described the data. An albumin concentration of ≤20 g/L decreased the probability of target attainment (PTA) by up to 20% across different dosing regimens and simulated creatinine clearances. A ceftriaxone dose of 1 g twice daily is likely therapeutic in patients with creatinine clearance of <100 mL/min infected with susceptible isolates (PTA, ~90%). Higher doses administered as a continuous infusion (4 g/day) are needed in patients with augmented renal clearance (creatinine clearance, >130 mL/min) who are infected by pathogens with a MIC of ≥0.5 mg/L. The ceftriaxone dose should be based on the patient's renal function and albumin concentration, as well as the isolate MIC. Hypoalbuminemia decreases the PTA in patients receiving intermittent dosing by up to 20%.
Topics: Adult; Albumins; Anti-Bacterial Agents; Ceftriaxone; Creatinine; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 35575578
DOI: 10.1128/aac.02189-21 -
Antimicrobial Agents and Chemotherapy Sep 2019High dosages of ceftriaxone are used to treat central nervous system (CNS) infections. Dosage adaptation according to the glomerular filtration rate is currently not... (Clinical Trial)
Clinical Trial
High dosages of ceftriaxone are used to treat central nervous system (CNS) infections. Dosage adaptation according to the glomerular filtration rate is currently not recommended. Ceftriaxone pharmacokinetics (PK) was investigated by a population approach in patients enrolled in a French multicenter prospective cohort study who received high-dose ceftriaxone for CNS infection as recommended by French guidelines (75 to 100 mg/kg of body weight/day without an upper limit). Only those with suspected bacterial meningitis were included in the PK analysis. A population model was developed using Pmetrics. Based on this model, a dosing nomogram was developed, using the estimated glomerular filtration rate (eGFR) and total body weight as covariates to determine the optimal dosage allowing achievement of targeted plasma trough concentrations. Efficacy and toxicity endpoints were based on previous reports, as follows: total plasma ceftriaxone concentrations of ≥20 mg/liter in >90% of patients for efficacy and ≤100 mg/liter in >90% of patients for toxicity. Based on 153 included patients, a two-compartment model including eGFR and total body weight as covariates was developed. The median value of the unbound fraction was 7.57%, and the median value of the cerebral spinal fluid (CSF)/plasma ratio was 14.39%. A nomogram was developed according to a twice-daily regimen. High-dose ceftriaxone administration schemes, used to treat meningitis, should be adapted to the eGFR and weight, especially to avoid underdosing using current guidelines. (This study has been registered at ClinicalTrials.gov under identifier NCT01745679.).
Topics: Anti-Bacterial Agents; Body Weight; Ceftriaxone; Cohort Studies; Cross Infection; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Male; Meningitis, Bacterial; Middle Aged; Monte Carlo Method; Nomograms; Prospective Studies; Treatment Outcome
PubMed: 31235630
DOI: 10.1128/AAC.00634-19 -
Antimicrobial Agents and Chemotherapy Jan 2022Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most...
Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment.
Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 h of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg of body weight every 12 h versus 24 h) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg, and peripheral volume is 19.6 L/70 kg. For both models, we found that allometric weight scaling, postmenstrual age, creatinine clearance, and daily highest temperature had significant effects on clearance. The presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 μg/ml for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 h is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the MICs (4 μg/ml).
Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Young Adult
PubMed: 34633847
DOI: 10.1128/AAC.01427-21 -
BMC Infectious Diseases Jun 2022The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) performs annual sentinel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically...
BACKGROUND
The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) performs annual sentinel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro-GASP results from 2019 (26 countries), linked to patient epidemiological data, and compared with data from previous years.
METHODS
Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST clinical breakpoints, where available) of 3239 N. gonorrhoeae isolates from 26 countries across the EU/EEA. Significance of differences compared with Euro-GASP results in previous years was analysed using Z-test and the Pearson's χ2 test was used to assess significance of odds ratios for associations between patient epidemiological data and antimicrobial resistance.
RESULTS
European N. gonorrhoeae isolates collected between 2016 and 2019 displayed shifting MIC distributions for; ceftriaxone, with highly susceptible isolates increasing over time and occasional resistant isolates each year; cefixime, with highly-susceptible isolates becoming increasingly common; azithromycin, with a shift away from lower MICs towards higher MICs above the EUCAST epidemiological cut-off (ECOFF); and ciprofloxacin which is displaying a similar shift in MICs as observed for azithromycin. In 2019, two isolates displayed ceftriaxone resistance, but both isolates had MICs below the azithromycin ECOFF. Cefixime resistance (0.8%) was associated with patient sex, with resistance higher in females compared with male heterosexuals and men-who-have-sex-with-men (MSM). The number of countries reporting isolates with azithromycin MICs above the ECOFF increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in 2019. Isolates with azithromycin MICs above the ECOFF (9.0%) were associated with pharyngeal infection sites. Following multivariable analysis, ciprofloxacin resistance remained associated with isolates from MSM and heterosexual males compared with females, the absence of a concurrent chlamydial infection, pharyngeal infection sites and patients ≥ 25 years of age.
CONCLUSIONS
Resistance to ceftriaxone and cefixime remained uncommon in EU/EEA countries in 2019 with a significant decrease in cefixime resistance observed between 2016 and 2019. The significant increase in azithromycin "resistance" (azithromycin MICs above the ECOFF) threatens the effectiveness of the dual therapy (ceftriaxone + azithromycin), i.e., for ceftriaxone-resistant cases, currently recommended in many countries internationally and requires close monitoring.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Azithromycin; Cefixime; Ceftriaxone; Ciprofloxacin; Drug Resistance, Bacterial; Female; Gonorrhea; Homosexuality, Male; Humans; Male; Microbial Sensitivity Tests; Neisseria gonorrhoeae; Pharyngitis; Sexual and Gender Minorities
PubMed: 35672671
DOI: 10.1186/s12879-022-07509-w -
CMAJ : Canadian Medical Association... Feb 2021
Topics: Abscess; Administration, Oral; Aged; Anti-Bacterial Agents; Ceftriaxone; Diabetes Mellitus, Type 2; Diagnosis, Differential; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Prostatic Diseases; Prostatic Hyperplasia; Tomography, X-Ray Computed
PubMed: 33619070
DOI: 10.1503/cmaj.200470 -
BMJ Case Reports May 2013A 61-year-old patient with diabetes had a bio-prosthetic aortic valve replacement 3 years before admission. He complained of lethargy, night sweats, decreased appetite...
A 61-year-old patient with diabetes had a bio-prosthetic aortic valve replacement 3 years before admission. He complained of lethargy, night sweats, decreased appetite and erratic blood glucose with no weight loss. He had splinter haemorrhage and a systolic ejection murmur at the aortic area. Chest and abdominal examination revealed no abnormality. The erythrocyte sedimentation rate and C reactive protein were raised. He had several sets of blood cultures and he was started on empirical vancomycin, rifampicin and gentamicin. Transthoracic echocardiography showed vegetation on the base of the anterior mitral leaflet, which was confirmed by a trans-oesophageal echocardiography. Blood culture was positive for Haemophilus aphrophilus, and he was started on ceftriaxone for 6 weeks instead of vancomycin and rifampicin and continued gentamicin for 2 weeks. Follow-up echocardiography showed no evidence of vegetations. The patient recovered completely and he was discharged home.
Topics: Aggregatibacter aphrophilus; Anti-Bacterial Agents; Ceftriaxone; Endocarditis, Bacterial; Humans; Male; Middle Aged; Pasteurellaceae Infections
PubMed: 23682079
DOI: 10.1136/bcr-2012-007359 -
Clinical Infectious Diseases : An... Oct 2022Antimicrobial-resistant Neisseria gonorrhoeae infections are a threat to public health. Novel strategies for combating such resistance include the development of...
Antimicrobial-resistant Neisseria gonorrhoeae infections are a threat to public health. Novel strategies for combating such resistance include the development of molecular assays to facilitate real-time prediction of antimicrobial susceptibility. Resistance to ciprofloxacin is determined by the presence of a single mutation at codon 91 of the gyrase A gene; molecular assays to guide therapy are commercially available. Resistance to cefixime is conferred via 1 of 6 critical mutations in either the mosaic penA gene or specific loci in the nonmosaic region. Resistance to ceftriaxone is conferred through mutations in 1 of 4 genes: penA, ponA, penB, and mtr; however, the ability to predict reduced susceptibility based on those genes varies by geographic region. Here, we highlight the work done toward the development of 3 such assays for ciprofloxacin, cefixime, and ceftriaxone, discuss the status of our current understanding and ongoing challenges, and suggest future directions.
Topics: Humans; Neisseria gonorrhoeae; Cefixime; Ceftriaxone; Microbial Sensitivity Tests; Gonorrhea; Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Bacterial
PubMed: 35818315
DOI: 10.1093/cid/ciac371 -
CMAJ : Canadian Medical Association... Nov 2021
Topics: Anti-Bacterial Agents; Ceftriaxone; Child, Preschool; Conservative Treatment; Female; Humans; Hydropneumothorax; Lung; Pneumonia; Radiography, Thoracic
PubMed: 34725121
DOI: 10.1503/cmaj.202468-f -
CMAJ : Canadian Medical Association... Jul 2021
Topics: Adult; Anti-Bacterial Agents; Ceftriaxone; Emergency Service, Hospital; Gonorrhea; Humans; Male; Neisseria gonorrhoeae; Pharynx; Polymerase Chain Reaction
PubMed: 34312175
DOI: 10.1503/cmaj.202183-f -
The Journal of Antimicrobial... Sep 2021The clinical response to ceftriaxone in patients with typhoid fever is significantly slower than with ofloxacin, despite infection with Salmonella enterica serovar Typhi...
BACKGROUND
The clinical response to ceftriaxone in patients with typhoid fever is significantly slower than with ofloxacin, despite infection with Salmonella enterica serovar Typhi (S. Typhi) isolates with similar susceptibilities (MIC 0.03-0.12 mg/L). The response to ofloxacin is slower if the isolate has intermediate susceptibility (MIC 0.25-1.0 mg/L).
OBJECTIVES
To determine the bactericidal activity and post-antibiotic effect (PAE) of ceftriaxone and ofloxacin against S. Typhi.
METHODS
The mean time to reach a 99.9% reduction in log10 count (bactericidal activity) and PAE of ceftriaxone and ofloxacin were determined for 18 clinical isolates of S. Typhi in time-kill experiments (MIC range for ofloxacin 0.06-1.0 mg/L and for ceftriaxone 0.03-0.12 mg/L).
RESULTS
The mean (SD) bactericidal activity of ofloxacin was 33.1 (15.2) min and 384.4 (60) min for ceftriaxone. After a 30 min exposure to ofloxacin, the mean (SD) duration of PAE was 154.7 (52.6) min. There was no detectable PAE after 1 h of exposure to ceftriaxone. For ofloxacin, bactericidal activity and PAE did not significantly differ between isolates with full or intermediate susceptibility provided ofloxacin concentrations were maintained at 4×MIC.
CONCLUSIONS
Infections with S. Typhi with intermediate ofloxacin susceptibility may respond to doses that maintain ofloxacin concentrations at 4×MIC at the site of infection. The slow bactericidal activity of ceftriaxone and absent PAE may explain the slow clinical response in typhoid.
Topics: Anti-Bacterial Agents; Ceftriaxone; Humans; Microbial Sensitivity Tests; Ofloxacin; Pharmaceutical Preparations; Salmonella typhi
PubMed: 34179968
DOI: 10.1093/jac/dkab215