ro13-9904 and Body-Weight

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

Concentrations of ceftriaxone in serum and intervertebral disc tissue were determined with high-pressure liquid chromatography in forty-five patients after a single intravenous loading dose of 1000 milligrams given at different intervals before an operation on the spine. The mean serum concentrations in this study corresponded well with reported values. The mean tissue concentrations were 5.6 micrograms per gram (95 per cent confidence interval, 3.6 to 6.8 micrograms per gram) one to less than two hours after administration of the antibiotic, 6.4 micrograms per gram (95 per cent confidence interval, 2.8 to 10.0 micrograms per gram) two to less than four hours, and 3.6 micrograms per gram (95 per cent confidence interval, 0.6 to 6.6 micrograms per gram) at fourteen to less than sixteen hours. These drug concentrations exceed the minimum inhibitory concentration that was effective against 90 per cent of the bacteria for methicillin-sensitive Staphylococcus aureus; for Streptococcus pyogenes, agalactiae, viridans, pneumoniae, and bovis; and for community-acquired Enterobacteriaceae. The average serum-to-tissue ratio was 191:1 at less than one-half hour and 13:1 at less than one and a half hours. The lower values of the 95 per cent confidence intervals for the concentration of the antibiotic exceeded the minimum inhibitory concentrations in the disc tissue against most susceptible bacteria during the period between one and a half and four hours, but a larger bolus would be needed to maintain this level for a longer period (such as in a longer operation) and as prophylaxis against methicillin-sensitive Staphylococcus aureus and coagulase-negative staphylococci.

Topics: Body Weight; Ceftriaxone; Diskectomy; Dose-Response Relationship, Drug; Humans; Intervertebral Disc; Methicillin Resistance; Microbial Sensitivity Tests; Premedication; Staphylococcus; Streptococcus; Surgical Wound Infection

PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (PARC,d+1; www.arcpredictor.com).. Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (±7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n = 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval.. A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and PARC,d+1 determined on the previous day. A high PARC,d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal PARC,d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% PARC,d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing.. Critically ill patients with CAP with a high PARC,d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.

Topics: Anti-Bacterial Agents; Body Weight; Ceftriaxone; Critical Illness; Humans; Pneumonia; Probability; Prospective Studies; Renal Insufficiency; Serum Albumin

Antibiotic exposure during pregnancy will adversely affect the growth of offspring; however, this remains controversial and the mechanism is poorly understood. To study this phenomenon, we added ceftriaxone sodium to the drinking water of pregnant rats and continuously monitored the body weight of their offspring. The results showed that compared with the control group, the offspring exposed to antibiotics during pregnancy had a higher body weight up to 3 weeks old but had a lower body weight at 6 weeks old. To determine the role of the gut microbiota and its metabolites in the growth of offspring, we collected feces for sequencing and further established that the experimental group has a different composition ratio of dominant bacteria at 6 week old, among which S24-7 correlated negatively with body weight and the metabolites that correlated with body weight-related unique flora were L-Valine, L-Leucine, Glutaric acid, N-Acetyl-L-glutamate, and 5-Methylcytosine. To further explore how they affect the growth of offspring, we submitted these data to Kyoto Encyclopedia of Genes and Genomes website for relevant pathway analysis. The results showed that compared with the control, the following metabolic pathways changed significantly: Valine, leucine, and isoleucine biosynthesis; Protein digestion and absorption; and Mineral absorption. Therefore, we believe that our findings support the conclusion that ceftriaxone sodium exposure in pregnancy has a long-lasting adverse effect on the growth of offspring because of an imbalance of gut microbiota, especially S24-7, via different metabolic pathways.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacteroidetes; Body Weight; Ceftriaxone; Female; Gastrointestinal Microbiome; Humans; Male; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley

Tularemia, a re-emerging, potential life threatening infectious disease, can present itself with nonspecific clinical symptoms including fever, chills and malaise. Taking a detailed history of exposure and a highly raised index of clinical suspicion are necessary to take the appropriate diagnostic and therapeutic steps in this setting. Here, a case report of typhoid tularaemia is presented.. A 53-year old male forester and farmer with protracted fever, abdominal pain, diarrhoea and loss of weight, who experienced productive cough and a pulmonary infiltrate later in the course of disease, was admitted for further investigation. Tularaemia was suspected only owing to history and confirmed by serologic testing more than three weeks after the beginning of the symptoms. The initial antibiotic therapy with ceftriaxone/doxycycline was switched to ciprofloxacin, resulting in the resolution of fever and symptoms.. Tularaemia has to be considered as a differential diagnosis in febrile patients, even more in cases with protracted fever. Since tularaemia is expanding geographically, involving more animal hosts and causing larger outbreaks, clinicians have to be aware of this potentially fatal disease.

Topics: Abdominal Pain; Anti-Bacterial Agents; Body Weight; Ceftriaxone; Ciprofloxacin; Cough; Diagnosis, Differential; Diarrhea; Doxycycline; Farmers; Fever; Francisella tularensis; Humans; Male; Middle Aged; Serologic Tests; Tularemia

Recent studies have demonstrated that antibiotics/or probiotics administration in early life play key roles on modulating intestinal microbiota and the alterations might cause long-lasting consequences both physiologically and immunologically. We investigated the effects of early life ceftriaxone, vancomycin and Bifidobacterium bifidum TMC3115 (TMC3115) treatment on intestinal microbiota and immunity both in neonates and adults even after termination of antibiotics exposure. We found that ceftriaxone and vancomycin, but not TMC3115, significantly altered the intestinal microbiota, serum total IgE level, and the morphology and function of the intestinal epithelium in the neonatal mice. In the adult stages, the diversity and composition of the intestinal microbiota were significantly different in the antibiotic-treated mice, and ceftriaxone-treated mice exhibited significantly higher serum total IgE and OVA-specific IgE levels. TMC3115 significantly mitigated the alteration of intestinal microbiota caused by ceftriaxone not vancomycin. Antibiotics and TMC3115 can differently modulate intestinal microbiota and SCFAs metabolism, affecting the development and function of the immunity and intestinal epithelium to different degrees in neonatal mice. Neonatal ceftriaxone-induced abnormal intestinal microbiota, immunity and epithelium could last to adulthood partly, which might be associated with the enhancement of host susceptibility to IgE-mediated allergies and related immune responses, TMC3115 may protect against the side effects of antibiotic treatment, at least partly.

Topics: Aging; Animals; Animals, Newborn; Bifidobacterium bifidum; Body Weight; Ceftriaxone; Cell Differentiation; Colony Count, Microbial; Cytokines; Enterocytes; Fatty Acids; Feces; Gastrointestinal Microbiome; Immunity; Immunoglobulin E; Intestines; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Ovalbumin; Phylogeny; Spleen; Vancomycin

Topics: Alcohol Drinking; Alcoholism; Amino Acid Transport Systems, Acidic; Animals; Anti-Bacterial Agents; Body Weight; Ceftriaxone; Central Nervous System Depressants; Drinking; Ethanol; Excitatory Amino Acid Transporter 2; Male; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Self Administration; Up-Regulation

There are few reports of in vivo muscle strength measurements in animal models of ICU-acquired weakness (ICU-AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU-AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU-AW is age-dependent in this model.. Young and old mice were injected intraperitoneally with E. coli and treated with ceftriaxone. Forelimb grip strength was measured at multiple time points, and the myosin/actin ratio in muscle was determined.. E. coli administration was not associated with grip strength decrease, neither in young nor in old mice. In old mice, the myosin/actin ratio was lower in E. coli mice at t = 48 h and higher at t = 72 h compared with controls.. This E. coli septic peritonitis mouse model did not induce decreased grip strength. In its current form, it seems unsuitable as a model for ICU-AW.

Topics: Actins; Age Factors; Aging; Animals; Anti-Bacterial Agents; Body Weight; Ceftriaxone; Disease Models, Animal; Escherichia coli; Intensive Care Units; Male; Mice; Mice, Inbred C57BL; Muscle Weakness; Muscle, Skeletal; Myosins; Peritonitis

The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis.. The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters.. The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two-compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms.. A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required.

Topics: Adolescent; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Body Weight; Ceftriaxone; Child; Child, Preschool; Computer Simulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Infant; Infant, Newborn; Japan; Microbial Sensitivity Tests; Models, Biological; Nonlinear Dynamics; Time Factors

Two patients, a girl and a boy, both aged 8.5 years, presented with serious side effects caused by ceftriaxone and co-trimoxazole, respectively. The first patientwas treated with ceftriaxone (100 mg/kg/day with a body weight of 35.6 kg) on suspicion of a neuroborreliosis, but developed an acute cholecystitis with cholelithiasis 3 weeks after the antibiotic had been withdrawn. He underwent a laparoscopic cholecystectomy. Ceftriaxone binds calcium in the biliary tract, forming biliary sludge or stones. The second patient developed thrombocytopenia during treatment with co-trimoxazole (58 mg/kg/day with a body weight of 25.4 kg) because of a urinary-tract infection. After discontinuation of the co-trimoxazole the thrombocytopenia resolved spontaneously. The pathophysiological mechanism involved may be either a direct toxic effect of trimethoprim or an immune-mediated reaction to sulfamethoxazole. According to current guidelines, the dosage of the drug was too high in both cases. It is important to ensure a correct dosage in children, since side effects are potentially dose-related.

Topics: Anti-Bacterial Agents; Body Weight; Ceftriaxone; Child; Cholelithiasis; Dose-Response Relationship, Drug; Female; Humans; Male; Thrombocytopenia; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

The course of bacterial titers, meningeal inflammation, behavioral abnormalities, and neuronal damage was studied in a mouse model of Streptococcus pneumoniae meningitis. At 24 h after injection of 10(4) colony-forming units (CFU) S. pneumoniae into the right forebrain, infected mice became severely lethargic. Bacterial titers in cerebrospinal fluid and cerebellum rose to 10(9) CFU/ml, with strong granulocyte invasion into the meninges and neuronal necroses in the neocortex, striatum and hippocampal formation. Meningeal inflammation and neuronal damage in intercellular cell adhesion molecule-1- and macrophage colony-stimulating factor-deficient mice was similar to that in wild-type littermates. Untreated, the infection was fatal. Wild-type mice treated earlier than 24 h after infection with ceftriaxone (2 mg every 12 h for 3 days) survived without apparent behavioral abnormalities. Delay of treatment beyond 30 h led to the death of more than 50% of the infected mice. This mouse model is suitable for therapeutic studies and for the investigation of inflammation in knockout mice. The neuronal damage resembles morphological abnormalities observed in humans.

Topics: Animals; Body Weight; Brain; Ceftriaxone; Cephalosporins; Disease Models, Animal; Glial Fibrillary Acidic Protein; Gliosis; Hyaluronan Receptors; Immunohistochemistry; Intercellular Adhesion Molecule-1; Leukocyte Count; Leukocytes; Macrophage Colony-Stimulating Factor; Macrophage-1 Antigen; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Streptococcus pneumoniae; Survival Rate; Treatment Outcome

Topics: Acute Disease; Body Weight; Ceftriaxone; Cephalosporins; Child; Humans; Injections, Intramuscular; Otitis Media

Monoclonal antibodies (MAbs) specific for O polysaccharide or core oligosaccharide/lipid A of Escherichia coli O111:B4 lipopolysaccharide (LPS) were compared in canine septic shock. Animals received O-specific, core-specific, or control murine IgG2a MAbs (or saline) before intraperitoneal implantation of an E. coli O111:B4-infected clot. Animals were further randomized to ceftriaxone or saline. O-specific MAb significantly reduced bacteremia and endotoxemia but not serum tumor necrosis factor. Core-specific MAb significantly increased mean arterial pressure from day 4 to 28 (P = .02). In dogs not receiving ceftriaxone, survival was enhanced by O-specific MAb (4/5) compared with core-specific MAb (0/5) and control (1/8) (P = .03). Survival rates were similar (P = .22) but survival was prolonged in antibiotic-treated animals also receiving O-specific MAb (P = .02 vs. core-specific MAb and controls) or core-specific MAb (P = .08 vs. controls). These data support the complex role of LPS in sepsis and the discrete functional effects of MAbs specific for different elements of LPS.

Topics: Animals; Antibodies, Monoclonal; Bacteremia; Body Temperature; Body Weight; Ceftriaxone; Disease Models, Animal; Dogs; Endotoxins; Escherichia coli; Hemodynamics; Lipopolysaccharides; O Antigens; Polysaccharides, Bacterial; Shock, Septic; Tumor Necrosis Factor-alpha