Ceftriaxone In Serum Research Articles

Population pharmacokinetics of unbound ceftriaxone in a critically ill population.

To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen. This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥60% of the dosing interval (ƒT>4xMIC ≥ 60%). 91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2±0.9L/h/1.85m2, the unbound renal clearance of ceftriaxone divided by the creatinine clearance 0.61±0.24, lean body mass corrected volume of distribution of the central compartment 0.82±0.21L/kg, and intercompartmental distribution rate constant from central to peripheral compartment 0.18±0.08h-1. Dosing simulations predicted ƒT>4 mg/L of 88% (95% CI: 69-100%) for 2,000 mg ceftriaxone once daily and ƒT>4 mg/L of 100% (95% CI: 100-100%) both for 1,000 mg twice daily and continuous infusion of 2,000 mg daily. We developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT>4 mg/L ≥60% for 1,000mg twice daily and 2,000 mg once daily or by continuous infusion.

Variability in the serum and tissue concentrations of pre-incisional ceftriaxone for surgery in paediatric population and outcome of surgical-site infections; An open labelled, prospective, non-randomized, analytical study

Studies have determined the serum concentration of ceftriaxone in the adult population, but there are only a few studies that measured the tissue concentrations. However, no studies have concurrently evaluated the serum and tissue concentrations of ceftrixaone in elective pediatric surgery patients. Therefore, our study was planned to evaluate the serum and tissue concentrations of single dose intravenous prophylactic ceftriaxone intra-operatively during an ongoing pediatric surgery and the outcome of surgical-site infections (SSIs). We did a correlation analysis to determine the relationship of various concentrations and surgery related risk factors with the outcome of SSIs. It was an open label prospective study in 50 patients who underwent elective pediatric surgery under prophylactic cover of ceftriaxone. Serum and tissue concentration were estimated by High Pressure Liquid Chromatography (HPLC). Subjects were observed for post operative complications including SSI. Serum and tissue concentrations of ceftriaxone were significant at test value of 4 ​mg/L. Tissue concentrations of ceftriaxone at incision (p ​= ​0.02) and closure (p ​= ​0.04) were significantly correlated with SSI but there was no significant association. The measured serum ceftriaxone concentrations were more than 20 times the susceptible minimum inhibitory concentration (MIC) at any given point of the surgery. On the other hand, this target level was achieved at the tissue levels in the majority of the patient. The factors associated with SSI were duration of surgery, wound category of contaminated clean type, the use of urinary catheter and implants in the surgery. An intra-operative re-dose, extension of dose or addition of another antibiotic may be considered for such patients.

Liquid Chromatography-Tandem Mass Spectrometry to Monitor Unbound and Total Ceftriaxone in Serum of Critically Ill Patients.

Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic Drug Monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce. The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings. In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, the limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/Pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval. The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation < 15.0% for concentrations between 0.2 - 400.0 mg/L. Ceftriaxone eluted at 1.94 min and ceftazidime, as internal standard, eluted at 1.42 min. Patients demonstrated a median unbound ceftriaxone fraction of 29.1% (IQR: 15.2 - 52.2). Day 1 of ceftriaxone treatment presented a median PK/PD target attainment of 100.0% (IQR: 81.1 - 100.0) for unbound ceftriaxone in serum, while for calculations based on total concentrations, this figure was 23.9% (IQR: 10.5 - 80.6). The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

450: Transplacental transfer of ceftriaxone in pregnant women with preterm premature rupture of membranes

The administrations of antibiotics to preterm premature rupture of membrane (PPROM) patients are standard treatment to prolong latency period and to prevent or treat infection. Ceftriaxone is one of the commonly used antibiotics for this purpose. However, pharmacokinetic study of antibiotics are sparse. The purpose of this study is to evaluate the transplacental transfer of ceftriaxone. Singleton pregnant women with PPROM were prospectively enrolled between August 2012 and April 2014. The diagnosis of PPROM was made with vaginal pooling or leakage of amniotic fluid or nitrazine test or amnisure test. After diagnosis of PPROM women were managed with triple antibiotics (ceftriaxone, clarithromycin, metronidazole). Both maternal and cord blood were obtained immediately at the time of delivery and stored at -70 °C deep freezer. Ceftriaxone concentration was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 31 cord-maternal serum pairs were available for analysis. The median umbilical cord and maternal serum concentrations were 6142 ng/mL and 6451 ng/mL, respectively. The median cord to maternal ratio of ceftriaxone was 0.97 (interquartile range 0.76-1.39). There was good correlation between cord and maternal serum ceftriaxone (Fig1, r=0.584, p< 0.01). There was a decreasing tendency of cord serum ceftriaxone as the hours from last injection of ceftriaxone to delivery increased (Fig2, r =-0.501, p< 0.01). The cord blood concentration of ceftriaxone was approximately 97% of maternal serum concentration and decreased as the hours from last injection of ceftriaxone to delivery increased.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Pharmacokinetic-pharmacodynamic comparison of ceftriaxone regimens in acute cholangitis

The most important factors determining the prognosis of patients with acute cholangitis (AC) are prompt biliary drainage and appropriate choice of antibiotics. This study was performed to evaluate whether dividing the number of doses based on the PK-PD theory contributes to better clinical outcome in the management of acute cholangitis. We measured ceftriaxone levels in blood and bile in 21 cases diagnosed with moderate-to-severe AC. Eleven cases were administered 2 g of ceftriaxone once-daily (group A) and 10 cases were given 1 g of ceftriaxone twice-daily (group B). The theoretical effect of ceftriaxone was evaluated by pharmacokinetic–pharmacodynamic (PK–PD) parameters. Clinical efficacy was evaluated by body temperature, white blood cell count and serum levels of C-reactive protein. Minimum level of ceftriaxone in serum (in mg/L) in groups A and B at 24 h after the first dose was 9.1 and 9.2, whereas that in bile was 2.9 and 2.5, respectively. The minimum inhibitory concentration (MIC) of ceftriaxone for all isolated bacteria was below the minimum serum and biliary concentration of ceftriaxone 24 h after the first administration (except for Enterococcus species). The MIC for isolated bacterial strains was <16 mg/L, which is the PK–PD breakpoint for ceftriaxone at 2 g/day. Both regimens showed clinical efficacy and did not contradict the effect predicted based on PK–PD.

Pharmacokinetics of ceftriaxone in patients undergoing continuous renal replacement therapy.

The duration of time for which the serum levels exceed the minimum inhibitory concentration (MIC) is an important pharmacokinetics (PK)/pharmacodynamics (PD) parameter correlating with efficacy for the antibiotic, ceftriaxone (CTRX). However, no reports exist regarding the PK or PD in patients undergoing continuous renal replacement therapy (CRRT). The purpose of this study was to examine the PK and safety of CTRX in patients undergoing CRRT in order to establish safer and more effective regimens. CTRX (1 g once a day) was intravenously administered four or more times to nine patients undergoing CRRT. Blood was collected after administration to measure CTRX concentrations in serum and the filtration fraction of CRRT by high-performance liquid chromatography. In addition to calculating PK parameters from serum CTRX, we (a) estimated by simulation CTRX concentrations when the dose interval was extended to once every 2 or 3 days, (b) calculated CTRX clearance via CRRT from CTRX concentrations in the filtration fraction, and (c) assessed the safety of CTRX use. Total body clearance and the half-life of CTRX were 7.46 mL/min (mean) and 26.5 h, respectively, in patients undergoing CRRT. CTRX was found in the filtration fraction, and the estimated clearance by CRRT was about 70% of total body clearance. Simulations revealed that even when the dose interval is increased to 2 or 3 days, CTRX would retain its efficacy. Our findings suggest that, depending on the condition of patients undergoing CRRT, CTRX could be used safely against pathogens with a CTRX MIC ≤2 µg/mL, even when extending the dose interval.

Pharmacokinetics of ceftriaxone after intravenous, intramuscular and subcutaneous administration to domestic cats

The pharmacokinetic properties of ceftriaxone, a third-generation cephalosporin, were investigated in five cats after single intravenous, intramuscular and subcutaneous administration at a dosage of 25 mg/kg. Ceftriaxone MICs for some gram-negative and positive strains isolated from clinical cases were determined. Efficacy predictor (t > MIC) was calculated. Serum ceftriaxone disposition was best fitted by a bicompartmental and a monocompartmental open models with first-order elimination after intravenous and intramuscular and subcutaneous dosing, respectively. After intravenous administration, distribution was fast (t1/2d 0.14 +/- 0.02 h) and moderate as reflected by the volume of distribution (V(d(ss))) of 0.57 +/- 0.22 L/kg. Furthermore, elimination was rapid with a plasma clearance of 0.37 +/- 0.13 L/h.kg and a t1/2 of 1.73 +/- 0.23 h. Peak serum concentration (Cmax), tmax and bioavailability for the intramuscular administration were 54.40 +/- 12.92 microg/mL, 0.33 +/- 0.07 h and 85.72 +/- 14.74%, respectively; and for the subcutaneous route the same parameters were 42.35 +/- 17.62 microg/mL, 1.27 +/- 0.95 h and 118.28 +/- 39.17%. Ceftriaxone MIC for gram-negative bacteria ranged from 0.0039 to >8 microg/mL and for gram-positive bacteria from 0.5 to 4 microg/mL. t > MIC was in the range 83.31-91.66% (10-12 h) of the recommended dosing interval (12 h) for Escherichia coli (MIC90 = 0.2 microg/mL).

Ceftriaxone Is an Efficient Component of Antimicrobial Regimens in the Prevention and Initial Management of Infections in End-Stage Renal Disease

Background: Infection is a frequent complication in patients with end-stage renal disease. The most common organisms isolated are gram-positive cocci and gram-negative bacilli. Therefore, the usual initial therapeutic approach in these situations is the simultaneous intravenous administration of vancomycin plus an aminoglycoside. This treatment's adverse effects include ototoxicity, nephrotoxicity, and less than ideal tissue penetrance. Methods: We assessed the efficacy of intravenous ceftriaxone in the prevention and in the initial empirical treatment of infections in end-stage renal disease patients, and tested the stability of blood levels of this antibiotic in this population. We studied 104 patients, 65 of them falling into the prevention group (1 g of ceftriaxone i.v. for 5 days) and 39 into the treatment group (1 g of ceftriaxone i.v. or intraperitoneally for 10-14 days). Results: Peak serum ceftriaxone concentrations were well above the minimal inhibitory concentration for 90% of strains. Trough serum concentrations of the drug prior to the next dose were also considerably in excess of the minimal inhibitory concentration. In the prevention group, 8 of 65 developed an infection, which was sensitive to ceftriaxone, whereas in 22 of the 39 patients from the treatment group, cultures showed organisms sensitive to ceftriaxone and in the remaining 17 patients sensitivity was not done. Conclusions: The present study demonstrates the efficacy of a simplified dosing schedule in achieving blood levels of the antibiotic well in excess of minimal inhibitory concentration of any of the organisms encountered. It also shows the usefulness of ceftriaxone in the prevention and/or treatment of bacterial infections and the lack of the side effects vancomycin and/or aminoglycosides possess.

In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345).

MK-826 (formerly L-749,345), is a potent 1-beta-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other beta-lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of beta-lactam antibiotics in reduction of Staphylococcus aureus CFU compared with results from nontreated controls (eliminating >/=4 log10 CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against Enterobacter cloacae (50% effective doses [ED50s] of 0.062 and 0.227 mg/kg, respectively) and Pseudomonas aeruginosa (ED50s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 microg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 microg . hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 microg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 microg . hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.

A comparative analysis of pharmacokinetics of ceftriaxone in serum and pleural fluid in humans: a study of once daily administration by intramuscular and intravenous routes.

Pleural fluid and serum pharmacokinetics of ceftriaxone were performed in thirteen patients with pleural effusion. One gram of ceftriaxone was administered once daily intravenously in six patients and intramuscularly in seven patients. Ceftriaxone concentrations were measured in serum and pleural fluids in both groups on the first day of administration and in four patients of the intramuscular group on the fourth day of administration. The mean serum peak concentration at 1 h was 199 mg/L (S.E.M. 63.2) in the iv group and 80.5 mg/L (S.E.M. 12.0) in the im group. The mean serum trough concentrations in the two groups at 24 h were 27.5 mg/L (S.E.M. 12.6) and 29.7 mg/L (S.E.M. 5.2) respectively. In the pleural fluid, mean peak concentration was 20.1 mg/L (S.E.M. 4.7) at 6 h in the iv group and 15.3 mg/L (S.E.M. 5.1) at 12 h in the im group. The mean trough concentration was 9.6 mg/L (S.E.M. 1.9) and 13.3 mg/L (S.E.M. 3.1) at 24 h in the two groups respectively. On the fourth day of intramuscular administration the serum and pleural fluid peak and trough concentrations were higher when compared with the first day, consistent with a cumulative effect. The serum and pleural fluid concentrations of ceftriaxone following intravenous and intramuscular administration were well above the MIC90 of most common respiratory pathogens indicating good penetration into extracellular spaces. Further, these serum and pleural fluid antibiotic concentrations could be maintained even after a single intramuscular injection of the drug, thus indicating its usefulness as a parenteral mode of therapy on a domicilliary basis with a significant cost-saving potential. In conclusion, intramuscular administration of ceftriaxone would appear to be a convenient method of administering parenteral therapy in lower respiratory tract infections in the hospital and community, with pharmacokinetics very similar to those exhibited by the intravenous route.

Serum bactericidal activity of ceftriaxone plus metronidazole against common intra-abdominal pathogens

The activity of ceftriaxone plus metronidazole against pathogens usually involved in intra-abdominal infections was studied. Metronidazole 1 g and ceftriaxone 1 g (as the sodium salt) were simultaneously administered i.v. over 30 minutes every 24 hours to 12 healthy volunteers for three doses. Serum samples were collected at baseline, just before the last dose, and 12, 16, 20, 22, and 24 hours after the start of infusion of the last dose. Serum bactericidal titers (SBTs) were performed in duplicate for each serum sample from 12 hours on. Serum ceftriaxone and metronidazole concentrations were determined by high-performance liquid chromatography, and the elimination rate and half-life were calculated for each antimicrobial in each volunteer. The minimum inhibitory concentrations (MICs) of each antibiotic for two strains each of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Bacteroides fragilis were determined by microdilution. Eleven volunteers completed the study. Ceftriaxone and metronidazole maintained SBTs of at least 1:4. Serum ceftriaxone concentrations remained above the MICs for E. coli, P. mirabilis, and K. pneumoniae, and serum metronidazole concentrations remained above the MIC for B. fragilis throughout the study. Ceftriaxone combined with metronidazole resulted in intense and prolonged activity against E. coli, P. mirabilis, K. pneumoniae, and B. fragilis.

Determination of ceftriaxone in aqueous humor and serum samples of differential-pulse adsorptive stripping voltammetry.

Differential-pulse adsorptive stripping voltammetry was used to determine ceftriaxone in serum and aqueous humour samples. The method involved extraction of the ceftriaxone from serum samples with an Amberlite XAD-2 column followed by elution with methanol. The recovery was 97.6% with a relative standard deviation of 3.3% at a ceftriaxone concentration of 90.9 microg 1(-1). Peak currents of ceftriaxone were measured with a hanging mercury drop electrode at -0.78 V versus an Ag-AgCl reference electrode in pH 3.0 Britton-Robinson buffer. The calibration graph was linear from 0.02 to 1300 microg 1(-1). The method was applied to cataract cases and ceftriaxone levels were measured in aqueous humour and serum samples from patients who had received 1 or 2 g of ceftriaxone intravenously. Aqueous humour was added to the polarographic cell directly. The amounts of ceftriaxone in the aqueous humour and serum samples with respect to time were measured. The pharmacokinetic profiles for 1 and 2 g were compared.

Simulated human serum profiles of one daily dose of ceftriaxone plus netilmicin in treatment of experimental streptococcal endocarditis.

We performed experiments in rats aimed at determining whether a combination of ceftriaxone (CRO) and netilmicin (NET), by using once-daily administration in rats, which simulated profiles of drug in human serum, was more effective than either agent alone in the treatment of endocarditis caused by viridans group streptococci. A programmable infusion pump system enabled the production of profiles of CRO in serum that simulate those found in humans after the intravenous administration of 2 g. The subcutaneous administration of 18 mg of NET per kg of body weight produced levels in the sera of rats comparable to those after the intravenous administration of a dose of 5 mg of NET per kg in humans. Rats with catheter-induced aortic vegetations were infected intravenously with two test strains, a CRO-susceptible Streptococcus sanguis strain (MICs of CRO and NET, 0.064 and 8 mg/liter, respectively) and a relatively CRO-resistant Streptococcus mitis strain (MICs of CRO and NET, 2 and 8 mg/liter, respectively). Against both strains, the combination of CRO and NET was synergistic in vitro as determined by time-kill curves. Treatment of rats was started 48 h postinfection and lasted for 3 days. CRO alone was effective against the susceptible strain (P < 0.001 compared with control animals) but was not effective against the resistant organism. A significantly enhanced antibacterial activity of the CRO-NET combination in reducing the valvular bacterial counts was observed with both test strains (P < 0.001). The synergistic effect was obtained with a single daily injection of NET which provided detectable levels in serum for only 8 h, suggesting that in vivo synergism in the treatment of infections caused by viridans group streptococci can be obtained without 24 h of aminoglycoside coverage. These experimental data might provide a rationale for clinical trials of a once-a-day dosing regimen in the treatment of streptococcal but nonenterococcal endocarditis.

Ceftriaxone pharmacokinetics in elderly subjects and penetration into epididymis.

In a prospective study, the epididymal penetration of ceftriaxone was evaluated in order to use it in the treatment of orchi-epididymitis in men. A bolus intravenous dose of 1 g of ceftriaxone was administered to 15 patients hospitalized for surgery as part of treatment for prostatic adenoma or prostatic cancer. Nine successive blood samples were collected in the interval from 0 to 24 h after administration, and epididymis samples were taken 0.75 h after administration. Concentrations of drug in all samples were assayed by a reverse-phase-ion pairing high-performance liquid chromatography method with UV detection. The results showed that the pharmacokinetics of ceftriaxone in serum did not differ from those determined previously in healthy volunteers. The terminal half-life was 6.9 +/- 1.7 h, and the mean residence time 9.5 +/- 2.3 h. The volume of distribution was 0.144 +/- 0.018 1 kg-1 and the total body clearance 1.17 +/- 0.29 l h-1. The concentrations in tissue reached 27.2 +/- 6 micrograms g-1 in righ epididymis, and 25.4 +/- 6.2 micrograms g-1 in left epididymis. The tissue-versus-serum concentration ratios ranged from 0.175 to 0.545 (mean value, 0.295 +/- 0.099). The concentrations in serum and tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ceftriaxone, particularly Neisseria gonorrhoeae and coliform bacteria.

Pharmacokinetics and protein binding of ceftriaxone during pregnancy.

The purpose of the present work was to study the pharmacokinetics and the protein binding (free fraction of the drug) of ceftriaxone (CTX) during pregnancy. Nine pregnant women (ages, 20 to 34 years) whose gestational ages ranged from 28 4/7 to 40 5/7 weeks were included. The diagnosis of infection was established in all cases; i.e., four women had chorioamnionitis and five women had pyelonephritis. The following triple antibiotic therapy was infused with the aim of achieving cure: CTX, 2 g once every 24 h (constant rate over 60 min); tobramycin, 3 mg/kg of body weight once every 24 h; and ornidazole, 1 g/day. Two series of blood samples were collected, i.e., during the first day of treatment (on day 1), to establish the primary pharmacokinetic profile of CTX, and at the plateau (on day 7), to evaluate a possible accumulation of the drug. This was an open, noncompartmental study, with each patient serving as her own control. Concentrations of total and unbound CTX in serum were measured by a high-performance liquid chromatographic method. Pharmacokinetic analysis was done by a noncompartmental method. Data were compared by a Wilcoxon t test (a P value of < or = 0.05 was considered significant). Data were also compared with those obtained for healthy subjects who received similar treatments. (i) The tolerance to treatment was excellent, and in all cases patients had a complete remission without premature delivery. (ii) No accumulation of CTX was noted during the treatment, and the profiles of the drug determined at days 1 and 7 were not significantly different.(iii) The pharmacokinetic parameters measured in pregnant patients during the third trimester of pregnancy were similar to those measured in healthy subjects. (iv) Residual concentrations of total and unbound CTX measured at 24 h were greater than the MICs for allegedly susceptible organisms, both on day 1 and at steady state. (v) During the final 3 months of pregnancy, the dosage schedule of CTX (2-g infusion per day) required no particular adjustment (i.e., neither a loading dose nor any increase in the maintenance dose.)

Serum protein binding and extravascular diffusion of methoxyimino cephalosporins. Time courses of free and total concentrations of cefotaxime and ceftriaxone in serum and pleural exudate

A new approach to the study of the distribution pharmacokinetics of variably bound beta-lactams is to plot the concentration time course of their free (dialysable) and total (free and bound) forms. In the present study, the 6-h concentration time course was plotted of the total and free concentrations of cefotaxime and ceftriaxone in serum and pleural exudate in 12 patients per group, after iv dosing with 1 g of either cefotaxime or ceftriaxone. Samples were taken at 0.5, 1, 1.5, 2, 3, 4 and 6h after dosing. The results of a study of similar design, but conducted over 24 h in ten patients per group, following iv dosing with either cefotaxime 1 g 12-hourly or ceftriaxone 1 g daily are also reported. Samples were taken at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 14, 16 and 24 h after dosing. Areas under the curve of free cefotaxime in pleural fluid were greater than those of free ceftriaxone, in both the 6 h (+54.6%) and 24 h studies (+29.8% after 12 h and +71.0% after 24 h). The free cefotaxime/free ceftriaxone Cmax ratio was 1.75 in the 6 h study. Cefotaxime was superior to ceftriaxone in terms of the diffusion of the free (antibacterially active) fraction into a typical inflammatory exudate. Assessment of the effects of protein binding must be taken into account in antibiotic pharmacokinetic profiles.

Ｃｅｆｔｒｉａｘｏｎｅ（ＣＴＲＸ）のヒト口腔組織移行について

For clinical application of Ceftriaxone (CTRX) in the oral field, a pharmacokinetic analysis was performed for CTRX concentration in the oral tissues and dose of 1g CTRX was administered to 37 patients in one shot by intravenous injection.The following results were obtained.1) The half life of CTRX in serum was thus calculated to be 7.412 hour.2) The highest concentrations of CTRX were 39.5μg/g in the gum, 19.0μg/g in the bone and 45.7μg/g in the cyst wall. The half life of CTRX was 4.09 hours in the gum, 2.26 hours in the bone and 7.29 hours in the cyst wall.The above results suggest that CTRX had the most favorable affinity of cephem antibiotics in the oral tissues.

Ion pair high-performance liquid chromatographic assay for ceftriaxone.

We developed a high-performance liquid chromatographic assay to measure ceftriaxone in serum, urine, and cerebrospinal fluid. Ion pairing was used because ceftriaxone is a relatively polar compound which is poorly retained on C18 columns in standard reverse-phase high-performance liquid chromatography and which produces trailing peaks in the absence of ion-pairing agents. The mobile phase was a combination of acetonitrile and water (46:54), adjusted to pH 9.0 with 10 mM K2HPO4, which contained 10 mM hexadecyltrimethylammonium bromide as the ion-pairing agent. Moxalactam (200 micrograms/ml) was used as the internal standard. A silica-packed precolumn (3 cm long) was used to prevent rapid deterioration of the analytical column (30 by 0.4 cm) by the alkaline pH of the mobile phase, and it significantly extended the life of the analytical column. The assay was linear with ceftriaxone concentrations of 1 to 250 micrograms/ml (r = 0.999) and correlated well with an agar diffusion bioassay (r = 0.990). Reproducibility was good, with intrarun coefficients of variation from 2.3 to 6.4% and interrun coefficients of variation from 3.2 to 21.4%. The absolute recoveries of ceftriaxone and moxalactam were 91 to 97 and 96 to 98%, respectively. No interferences were observed with more than 40 commonly prescribed drugs, including 10 cephalosporins (cefotaxime, cefoperazone, ceftazidime, ceftizoxime, cefoxitin, cefamandole, cephalothin, cefazolin, cephapirin, and cephalexin), or with sera from patients with renal or hepatic disease.

Once daily ceftriaxone for central nervous system infections and other serious pediatric infections.

Ceftriaxone has a very long serum half-life and enhanced in vitro activity against common pediatric pathogens. Therefore we evaluated the efficacy and safety of once daily ceftriaxone therapy in 57 children with serious infections including: meningitis (26 patients); ventriculitis (3); pyelonephritis (7); osteomyelitis (6); abscess (4); septic arthritis (3); sepsis (2); and miscellaneous infections (6). The most common isolates were Haemophilus influenzae (23), Escherichia coli (9) and Staphylococcus aureus (8). Ceftriaxone was given intravenously or intramuscularly in a dose of 50 mg/kg for non-central nervous system (CNS) infections. Patients with CNS infections received an initial dose of 100 mg/kg followed by 80 mg/kg 12 hours later and once daily thereafter. In a limited number of patients no major differences in serum ceftriaxone concentrations were found after intravenous or intramuscular injection. Of 57 patients with pathogens isolated 55 were completely cured; in one patient with Klebsiella pneumoniae ventriculitis, intraventricular gentamicin was briefly added to the regimen. Another patient with an anaerobic liver abscess recovered after metronidazole was administered. In three patients a delayed response to ceftriaxone was noted. One patient with previous recurrent infections had a second episode of H. influenzae meningitis 22 days after cessation of therapy. Clinical side effects were noted in 10 of 71 patients (including 14 treated patients who had negative cultures). Seven patients had diarrhea, one each had fever or rash and one had fever, rash and arthralgia. Laboratory side effects in 16 of 71 patients included eosinophilia (7), thrombocytosis (7), elevated liver enzymes (4) and leukopenia and neutropenia (2).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of ceftriaxone in serum and gynecological tissues.

In order to evaluate the pharmacokinetics of ceftriaxone (Rocephin) in serum and gynecological tissues, intravenous injections of 2 g of ceftriaxone were administered to 3 groups, numbering 6 patients each, at 2-, 12-, and 24-hour intervals prior to surgery (hysterectomy and annexectomy) for noninfectious pathology. Even 24 h after intravenous administration of 2 g of ceftriaxone, both serum and gynecological tissue concentrations are well above the MIC90 for the majority of pathogens responsible for gynecological infections excepting Streptococcus faecalis and Bacteroides fragilis.