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PubMed1993

The in vitro antibacterial activity of ceftriaxone against Streptococcus pyogenes is unrelated to penicillin-binding protein 4.

The in vitro activities of penicillin and ceftriaxone were compared against 29 strains of Streptococcus pyogenes with the result that ceftriaxone showed greater activity than penicillin. The morphological changes induced by 1/2 and 1x MIC concentrations of penicillin and ceftriaxone, respectively, were very similar using scanning electron microscopy. Competitive binding studies using 'cold' penicillin or ceftriaxone as inhibitors of radiolabeled penicillin binding demonstrated that ceftriaxone had a very low affinity for penicillin binding protein (PBP) 4 compared to that of penicillin. Since ceftriaxone had greater antibacterial activity, this suggests that PBP 4 may not be important to the in vitro activity of ceftriaxone. In contrast, the IC50 for ceftriaxone was much lower (> 200 fold) for PBPs 2 and 3 compared to PBP 4, suggesting greater avidity of these high molecular mass PBPs for ceftriaxone. These data may at least in part explain the superior in vitro activity of ceftriaxone compared to penicillin against S. pyogenes. These data, together with the observation that PBP 1 was saturated at a lower concentration of penicillin than any of the other PBPs, suggest that the inhibition of PBPs 1, 2, and 3 mediates the bactericidal activity of beta-lactam antibiotics against group A streptococci.

Bacterial Proteins↗

PubMed1981

In vivo activity of ceftriaxone (Ro 13-9904), a new broad-spectrum semisynthetic cephalosporin.

Ceftriaxone (Ro 13-9904) was compared with other newer beta-lactam antibiotics for activity in experimental infections of mice with Enterobacteriaceae, Haemophilus influenzae, Pseudomonas aeruginosa, and gram-positive bacteria. Overall, ceftriaxone was equal or superior to cefotaxime and cefoperazone against systemic infections. All three drugs were highly potent against most organisms but were considerably less active against P. aeruginosa. However, ceftriaxone tended to be more active than the other two agents against 8 of the 10 P. aeruginosa strains tested. Ceftriaxone, cefmenoxime (SCE 1365), and moxalactam were all highly active against systemic infections with 16 strains of Enterobacteriaceae, whereas ceftriaxone was more active against infections with two strains of streptococci. When the drugs were administered at various time intervals before infection, ceftriaxone was superior to cefotaxime, cefmenoxime, and moxalactam. This suggested that ceftriaxone might be eliminated from mice more slowly than the other drugs. In the case of cefotaxime, this was directly confirmed by microbiological assays of plasma samples. In a murine meningitis model induced by Klebsiella pneumoniae or Streptococcus pneumoniae, ceftriaxone was more active than ampicillin or cefotaxime. Ceftriaxone was more active than ampicillin, cefotaxime, piperacillin, cefamandole, or carbenicillin in a pneumococcal, pneumonia model in mice. These studies indicate that ceftriaxone is a potent, broad-spectrum cephalosporin with unusual pharmacokinetic properties.

Animals↗

PubMed1987

Comparative efficacy of cefotiam, cefmenoxime, and ceftriaxone in experimental endocarditis and correlation with pharmacokinetics and in vitro efficacy.

To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three cephalosporins, cefotiam, cefmenoxime, and ceftriaxone, in a rabbit model of experimental Escherichia coli endocarditis after 4 days of treatment. The MBCs of cefotiam, cefmenoxime, and ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves at 10 times the MBC were similar for the three cephalosporins. In serum, the elimination half-life of ceftriaxone was twice as much as the elimination half-life of cefotiam or cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively). Ceftriaxone was much more effective than cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with cefotiam and 2.41 +/- 2.6 with ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although ceftriaxone and cefmenoxime exhibited a similar rate of killing and percentage of protein binding, ceftriaxone was more effective than cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for ceftriaxone, but not for cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum cephalosporin may be effective in severe gram-negative infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared drug with the same intrinsic activity.

Animals↗

PubMed1994

Ceftriaxone protects against tobramycin nephrotoxicity.

The effect of ceftriaxone on tobramycin-induced nephrotoxicity was investigated. Female Sprague-Dawley rats were treated during 4 and 10 days with saline (NaCl, 0.9%), ceftriaxone at a dose of 100 mg/kg of body weight/12 h subcutaneously, tobramycin at doses of 40 and 60 mg/kg/12 h intraperitoneally, or the combination ceftriaxone-tobramycin. Creatinine levels in serum were significantly higher in animals treated with tobramycin alone given at 60 mg/kg/12 h during 10 days, compared with control animals (P < 0.01) or animals receiving the combination tobramycin-ceftriaxone (P < 0.01). After 10 days of treatment, ceftriaxone did not accumulate in renal tissue but did reduce the renal intracortical accumulation of tobramycin (P < 0.05). Tobramycin given alone at either 40 or 60 mg/kg/12 h induced a significant inhibition of sphingomyelinase activity compared with control animals (P < 0.05). However, this enzyme activity was significantly less inhibited when tobramycin was injected in combination with ceftriaxone (P < 0.05). Ceftriaxone alone had no effect on the activity of this enzyme. The [3H]thymidine incorporation into the DNA of renal cortex was also significantly lower in animals treated with tobramycin-ceftriaxone compared with animals receiving tobramycin alone (P < 0.05). The 24-h urinary excretion of beta-galactosidase was significantly reduced in animals treated with the combination tobramycin-ceftriaxone compared with the administration of tobramycin alone at 40 and 60 mg/kg/12 h after 5 and 10 days (P < 0.05). Histologically, ceftriazone induced very few cellular alterations and reduced considerably the presence of typical signs of tobramycin nephrotoxicity. This investigation demonstrated that ceftriaxone protects animals against tobramycin-induced nephrotoxicity.

Animals↗

PubMed1996

Penetration of ceftriaxone (1 or 2 grams intravenously) into mediastinal and cardiac tissues in humans.

Penetration of ceftriaxone into heart tissues (valves, myocardium, auricles, and pericardium) and mediastinal tissues (fat and sternal bone) was evaluated after two regimens of ceftriaxone administration. Ten patients (group 1) were given 1,000 mg of ceftriaxone intravenously 30 min before anesthesia. Ten other patients (group 2) received the same dose and then a second 1,000-mg dose at the time of initiation of cardiopulmonary bypass. Similar and very satisfactory penetrations of ceftriaxone into tissue were observed for both groups. During opening and closure of the thorax, mean ceftriaxone concentration was in excess of the MIC at which 90% of the potential pathogens were inhibited (> or = 4 micrograms/g) in the thoracic fat, the sternal bone, and the pericardium. No significant differences between the two administration regimens in penetration of ceftriaxone into tissue were observed. During cardiopulmonary bypass, the ceftriaxone concentration was > or = 4 micrograms/g in the myocardium, the endocardium, and the auricle. The regimen of ceftriaxone administration did not significantly influence penetration of the drug into heart tissues. However, for some patients in the two groups and mainly in the sternal bone at the time of thorax closure (6 patients in group 1 and 5 patients in group 2), ceftriaxone levels in tissues were less than the MICs (4 micrograms/g) for some potential pathogens (methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis). During the different steps of the surgical procedures, all (10 of 10) patients in each group had tissue ceftriaxone levels greater than the MICs for gram-negative aerobic bacilli (0.1 microgram/g), except for Pseudomonas spp.

Bone and Bones↗

PubMed2000

Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis.

STUDY OBJECTIVE: To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy. DESIGN: Prospective, outpatient study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight patients receiving hemodialysis. INTERVENTION: We performed controlled clearance studies with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). MEASUREMENTS AND MAIN RESULTS: Subjects received ceftriaxone 1000 mg intravenously before the start of a clearance study. The concentration of ceftriaxone in multiple plasma and dialysate-ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (Cl(diffusion)) and sieving coefficients (SC) of ceftriaxone, urea, and creatinine were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and patient as a random effect. The fraction of ceftriaxone bound to plasma proteins was 43 +/- 15% (range 13-92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (f(up)) at the time that SCs were determined was significantly lower in the PS group (0.16 +/- 0.07) than the AN69 group (0.30 +/- 0.17, p<0.01), but similar to that in the PMMA group (0.27 +/- 0.12). Despite the higher f(up), the SC of unbound ceftriaxone with the AN69 filter (0.48 +/- 0.13) was significantly lower than values for the PMMA (0.86 +/- 0.33) and PS (0.82 +/- 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea and unbound ceftriaxone increased significantly only for the PMMA (p=0.006) and PS (p=0.015) filters when the ultrafiltration rate was increased. Significant linear relationships (p<0.0001) were observed between Cl(diffusion) of unbound ceftriaxone and clearance of urea for all three filters: AN69 slope = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relationship for the AN69 filter was significantly lower than for the other two filters. CONCLUSION: Ceftriaxone clearance was significantly increased and membrane dependent during continuous venovenous hemofiltration and continuous venovenous hemodialysis. Thus individual ceftriaxone dosages for patients receiving continuous renal replacement therapies should incorporate extracorporeal clearance.

Adult↗

PubMed2006

Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients.

OBJECTIVES: To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices. METHODS: Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They received short intravenous infusions of ceftriaxone 1 or 2 g every 48 hours for bronchopneumonia immediately after the dialysis session. Total plasma concentrations of ceftriaxone were analysed with a population pharmacokinetic approach using nonlinear mixed-effects modelling. Free drug concentrations were derived from published binding parameters in order to estimate the time when they exceed the minimum inhibitory concentration (MIC). RESULTS: The pharmacokinetics were best described by a two-compartment model. None of the covariates tested (age, bodyweight, height, sex, body mass index, albumin) influenced the pharmacokinetic parameters. The estimated population pharmacokinetic parameters (interindividual variability [percentage of coefficient of variation]) were clearance 0.36 L/h (48%), volume of distribution of the central compartment 4.53 L (47%), intercompartmental clearance 10.8 L/h and volume of distribution of the peripheral compartment 9.54 L (63%). The terminal elimination half-life (t(1/2)beta) from plasma was 27.5 hours. The mean (range) times when the free drug concentration exceeded the MIC (T>MIC) following ceftriaxone 1 g infusion were 60.3 (53.0-67.7) hours and 2.5 (1.0-3.9) hours for the breakpoints 1 and 8 mg/L (based on free drug concentration), respectively. After administration of ceftriaxone 2 g, the T>MIC was 88.5 (78.8-98.3) hours and 17.7 (13.3-22.0) hours for the breakpoints 1 and 8 mg/L, respectively. The simulated free drug concentrations (median, first and third quartile) for 48 and 72 hours following the first dose of ceftriaxone 1g were 1.11, 0.63 and 1.89 mg/L, and 0.63, 0.28 and 1.18 mg/L, respectively. For ceftriaxone 2g infusion, the simulated free concentrations (median, first and third quartile) at 48 and 72 hours were 2.50, 1.40 and 4.52 mg/L, and 1.37, 0.60 and 2.70 mg/L, respectively. CONCLUSIONS: On the basis of decreased clearance in haemodialysed patients, it can be argued that the dose of ceftriaxone should be decreased or the delay between doses should be increased. However, taking into account pharmacodynamic considerations, this study showed that following intravenous administration of ceftriaxone 1 g after each dialysis session, some patients were at risk of achieving a concentration below the MIC (1 mg/L), particularly if the second administration occurred 72 hours after the first dosing. Thus, a dose of ceftriaxone 2 g intravenously is recommended immediately following dialysis, particularly in patients with severe infections or when the dosing interval will be higher than 48 hours.

Adult↗

PubMed1984

Ceftriaxone. A review of its antibacterial activity, pharmacological properties and therapeutic use.

Ceftriaxone is a new 'third generation' semisynthetic cephalosporin with a long half-life which has resulted in a recommended once daily administration schedule. It is administered intravenously or intramuscularly and has a broad spectrum of activity against Gram-positive and Gram-negative aerobic, and some anaerobic, bacteria. The activity of ceftriaxone is generally greater than that of the 'first' and 'second generation' cephalosporins against Gram-negative bacteria, but less than that of the earlier generations of cephalosporins against many Gram-positive bacteria. Although ceftriaxone has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy in pseudomonal infections. Ceftriaxone has been effective in treating infections due to other 'difficult' organisms such as multidrug-resistant Enterobacteriaceae. Ceftriaxone was effective in complicated and uncomplicated urinary tract infections, lower respiratory tract infections, skin, soft tissue, bone and joint infections, bacteraemia/septicaemia, and paediatric meningitis due to susceptible organisms. In most of these types of infections once-daily administration appears efficacious. Results were also encouraging in a few patients with ear, nose and throat, intra-abdominal, obstetric and gynaecological infections, and adult meningitis, but conclusions are not yet possible as to the efficacy of the drug in these indications due to limited experience. A single intramuscular dose of ceftriaxone has been compared with standard therapy for gonorrhoea due to non-penicillinase-producing and penicillinase-producing strains of Neisseria gonorrhoeae and shown to be highly effective. In a few small trials the comparative efficacy of ceftriaxone and other antibacterials has been assessed in other types of infections and in perioperative prophylaxis in patients undergoing surgery. Few significant differences in response rates were found between therapeutic groups in these comparative studies, but larger well-designed studies are needed to more clearly assess the comparative efficacy of ceftriaxone and other antimicrobials, especially the aminoglycosides and other 'third generation' cephalosporins, and to confirm the apparent lack of serious side effects with ceftriaxone. If more widespread use confirms the safety and efficacy of ceftriaxone, it will offer an important alternative, particularly for the treatment of serious infections due to multidrug-resistant Gram-negative bacteria and in situations where the long half-life of the drug could result in worthwhile convenience and cost benefits.

Aging↗

PubMed1988

Effect of probenecid on the elimination and protein binding of ceftriaxone.

The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CLTS) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t1/2T (beta)) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CLFR) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CLFR was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CLFNR) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CLFS) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.

Adult↗

PubMed2003

Does dexamethasone affect ceftriaxone [corrected] penetration into cerebrospinal fluid in adult bacterial meningitis.

Trough cerebrospinal fluid (CSF) ceftriaxone concentrations were measured daily to investigate the effect of dexamethasone on ceftriaxone penetration into CSF in adult patients with acute bacterial meningitis. Patients were divided into two groups in this double blind randomized study. In group 1 (n=6) patients were given ceftriaxone with dexamethasone whereas in group 2 (n=6) patients were only administered ceftriaxone. Plasma and CSF samples were collected at 24, 48, 72, 96 and 264 h following the study treatments. The trough CSF ceftriaxone concentrations were measured using high performance liquid chromatography (HPLC) and microbiological assay. CSF ceftriaxone concentrations were 3.21 mg/l at 24 h in group 1 and 4.85 mg/l at the same time in group 2 by HPLC. Although microbiological assay results were lower than HPLC the trough CSF ceftriaxone concentrations in dexamethasone group were at least 10(3) times higher than the minimum inhibitory concentrations of the susceptible strains. It was concluded that the ceftriaxone concentration in CSF was adequate and ceftriaxone penetration was not significantly affected by concomitant dexamethasone use in adult patients with acute bacterial meningitis.

Adolescent↗

PubMed2000

Ceftriaxone-resistant salmonella infection acquired by a child from cattle.

BACKGROUND: The emergence of resistance to antimicrobial agents within the salmonellae is a worldwide problem that has been associated with the use of antibiotics in livestock. Resistance to ceftriaxone and the fluoroquinolones, which are used to treat invasive salmonella infections, is rare in the United States. We analyzed the molecular characteristics of a ceftriaxone-resistant strain of Salmonella enterica serotype typhimurium isolated from a 12-year-old boy with fever, abdominal pain, and diarrhea. METHODS: We used pulsed-field gel electrophoresis and analysis of plasmids and beta-lactamases to compare the ceftriaxone-resistant S. enterica serotype typhimurium from the child with four isolates of this strain obtained from cattle during a local outbreak of salmonellosis. RESULTS: The ceftriaxone-resistant isolate from the child was indistinguishable from one of the isolates from cattle, which was also resistant to ceftriaxone. Both ceftriaxone-resistant isolates were resistant to 13 antimicrobial agents; all but one of the resistance determinants were on a conjugative plasmid of 160 kb that encoded the functional group 1 beta-lactamase CMY-2. Both ceftriaxone-resistant isolates were closely related to the three other salmonella isolates obtained from cattle, all of which were susceptible to ceftriaxone. CONCLUSIONS: This study provides additional evidence that antibiotic-resistant strains of salmonella in the United States evolve primarily in livestock. Resistance to ceftriaxone, the drug of choice for invasive salmonella disease, is a public health concern, especially with respect to children, since fluoroquinolones, which can also be used to treat this disease, are not approved for use in children.

Animals↗

PubMed1989

Use of beta-lactamase-producing anaerobes to prevent ceftriaxone from degrading intestinal resistance to colonization.

Six adult volunteers were given 1 g/d of intravenous ceftriaxone for 5 d (consecutive). Ceftriaxone and beta-lactamase activities were assayed in fecal samples obtained before and during drug administration, and anaerobic bacteria, Enterobacteriaceae, and fungi were counted. In two volunteers, no fecal beta-lactamase activity was detected, but ceftriaxone was present during treatment at concentrations of 1.8-2.0 mg/g of feces. Concomitantly, fecal counts of anaerobes in these volunteers dropped from 10.5 to less than 8 log10 colony-forming units (cfu)/g of feces, and those of Candida species increased more than 100-fold. However, in the feces of the four other volunteers, beta-lactamase activity was high during ceftriaxone administration, but no ceftriaxone was detected. In these volunteers, ceftriaxone administration was not followed by any significant change in counts of anaerobes or Candida species. This appeared to be due to the intraintestinal hydrolysis of ceftriaxone by resident beta-lactamase-producing anaerobes. In gnotobiotic mice associated with a human fecal flora containing no beta-lactamase-producing anaerobes, it was possible to prevent the deleterious effects of ceftriaxone on intestinal microbial composition and on colonization resistance (against a strain of Candida albicans and one of ceftriaxone-resistant Enterobacter cloacae) by feeding the animals with an association of four beta-lactamase-producing anaerobic strains.

Adult↗

PubMed1990

Incidence of gallbladder lithiasis after ceftriaxone treatment.

Ceftriaxone has potent activity against a broad range of Gram-positive and Gram-negative bacteria. While it is eliminated mainly by the kidney, 10-20% of the drug is eliminated in the bile and ceftriaxone salt precipitates have been described in the gallbladder of animals dosed with ceftriaxone. The purpose of the present study was to investigate the incidence of biliary lithiasis 6 and 12 months after treatment with ceftriaxone and to compare it with that in patients treated with amoxycillin/clavulanate. Biliary ultrasonography was performed at the start of treatment, at 6 months and at 12 months after the beginning of the study. One hundred patients were randomized and 74 were evaluable: 34 were given amoxycillin/clavulanate, 40 ceftriaxone. Gallbladder lithiasis developed in one patient 12 months after the amoxycillin/clavulanate treatment and in none in the ceftriaxone treatment arm. Biliary precipitate during ceftriaxone treatment was not looked for because this phenomenon was not known at the beginning of the study, but gallbladder precipitation that was seen in two patients given ceftriaxone during and at the end of treatment, respectively, resolved spontaneously. In conclusion, ceftriaxone treatment does not appear to lead to gallstone formation more often than an antibiotic that is not eliminated through the bile.

Adolescent↗

PubMed1984

Comparative pharmacokinetics of YM-13115, ceftriaxone, and ceftazidime in rats, dogs, and rhesus monkeys.

The pharmacokinetics of YM-13115, ceftriaxone, and ceftazidime were studied in rats, dogs, and rhesus monkeys (only YM-13115 and ceftriaxone were studied in rhesus monkeys). The plasma half-lives in rats were 48 min for YM-13115, 34 min for ceftriaxone, and 14 min for ceftazidime. In dogs, they were 21.9 min for YM-13115, 50.7 min for ceftriaxone, and 49.0 min for ceftazidime. In monkeys, they were 5.30 h for YM-13115 and 3.40 h for ceftriaxone. The 24-h urinary recoveries in rats were 26.7% of the dose for YM-13115, 32.0% for ceftriaxone, and 97.1% for ceftazidime. In dogs, they were 13.3% for YM-13115, 62.5% for ceftriaxone, and 86.3% for ceftazidime. In monkeys, they were 22.5% for YM-13115 and 29.3% for ceftriaxone. The 24-h biliary recoveries in rats were 72.2% for YM-13115, 61.8% for ceftriaxone, and 0.63% for ceftazidime.

Animals↗

PubMed1985

Comparison of ceftriaxone and ampicillin plus chloramphenicol for the therapy of acute bacterial meningitis.

Ceftriaxone, a new third-generation cephalosporin, appears to be promising for the therapy of acute bacterial meningitis. The 90% MBCs of ceftriaxone against 54 recent cerebrospinal fluid isolates of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae were less than or equal to 0.06 to 0.25 micrograms/ml. We examined the efficacy and safety of ceftriaxone therapy of meningitis in Bahia, Brazil. The study was conducted in two phases; in phase A, ceftriaxone was coadministered with ampicillin. The mean cerebrospinal fluid concentrations of ceftriaxone 24 h after an intravenous dose of 80 mg/kg were 4.2 and 2.3 micrograms/ml on days 4 to 6 and 10 to 12 of therapy, respectively. These concentrations were 8- to more than 100-fold greater than the 90% MBCs against the relevant pathogens. In phase B, ceftriaxone (administered once daily at a dose of 80 mg/kg after an initial dose of 100 mg/kg) was compared with conventional dosages of ampicillin and chloramphenicol in a prospective randomized trial of 36 children and adults with meningitis. The groups were comparable based on clinical, laboratory, and etiological parameters. Ceftriaxone given once daily produced results equivalent to those obtained with ampicillin plus chloramphenicol, as judged by cure rate, case fatality ratio, resolution with sequelae, type and severity of sequelae, time to sterility of cerebrospinal fluid, and potentially drug-related adverse effects. The cerebrospinal fluid bactericidal titers obtained 16 to 24 h after ceftriaxone dosing were usually 1:512 to greater than 1:2,048 even late in the treatment course, compared with values of 1:8 to 1:32 in patients receiving ampicillin plus chloramphenicol. Ceftriaxone clearly deserves further evaluation for the therapy of meningitis; the optimal dose, dosing frequency (every 12 h or every 24 h), and duration of therapy remain to be determined.

Ampicillin↗

PubMed1987

Contribution of beta-lactamase hydrolysis and outer membrane permeability to ceftriaxone resistance in Enterobacter cloacae.

Mechanisms of ceftriaxone resistance were examined in Enterobacter cloacae. Clones were selected from four strains: susceptible (S), resistant (R1), selected by plating on ceftriaxone-containing agar, and highly resistant (R2), selected in ceftriaxone-treated mice infected with S clones. According to 14C-labeled beta-lactam binding assays, ceftriaxone resistance was not associated with altered target proteins. R1 and R2 clones stably produced 50 to 1,500 times more beta-lactamase than S clones; this production increased after cefoxitin induction in all S and some R1 clones. Experiments conducted with strain 218 suggested that ceftriaxone resistance involved beta-lactamase hydrolysis. Half-lives for the beta-lactamase-beta-lactam complexes at 37 degrees C were 0.4 and 2.2 min for ceftriaxone and Sch 34343, a drug not affected by the resistance, respectively; in chromatography experiments, 218 intact R1 cells (2 x 10(9) to 3 x 10(9) CFU) suspended in ceftriaxone-containing buffer (2 micrograms/ml) hydrolyzed 80% of the antibiotic in 30 min. Three observations also suggested decreased permeability in some clones, (i) Most of the R1 and R2 clones showed decreased expression of outer membrane proteins of 37,000 to 38,000 molecular weight (37K to 38K proteins) by electrophoresis, often associated with increased amounts of 42K protein. (ii) [14C]Sch 34343 labeling of intact cells proceeded more slowly in 218 R2 (with altered 37K to 38K proteins) than in 218 R1 (without this alteration), a difference persisting after competition with unlabeled cloxacillin. Delays in binding were not caused by different enzymatic activities, since 218 R1 and 218 R2 produce, in similar amounts, beta-lactamases undistinguishable in isoelectric point and Km of cephaloridine. (iii) Intact cells from 218 R2 hydrolyzed ceftriaxone more slowly (20% in 30 min) than did those from 218 R1. In 218 R1, beta-lactamase overproduction was responsible for a 15- to 200-fold increase in the MIC's of ceftriaxone, ceftazidime, carbenicillin, piperacillin, moxalactam, aztreonam, carumonam, and BMY 28142. Imipenem and Sch 34343 were not affected; an additional three- to fivefold increase in the MIC's of these antibiotics (with the exception of piperacillin, imipenem, Sch 34343), seen with 218 R2, was associated with decreased permeability.

Anti-Bacterial Agents↗

PubMed1989

Reduction in biliary excretion of ceftriaxone by diclofenac in rabbits.

The effects of diclofenac, a nonsteroidal anti-inflammatory drug, on biliary excretion of ceftriaxone were evaluated in rabbits. In a previous study, we demonstrated that diclofenac increased the extravascular diffusion and antibacterial efficacy of ceftriaxone without any effect on serum protein binding and urinary excretion of this antibiotic. We perfected a surgical procedure that allowed the study of biliary secretion in conscious rabbits with a stable hemodynamic state. The kinetic study was carried out on the fourth day of treatment with ceftriaxone alone (30 mg/kg per day given intramuscularly; group 1) or combined with diclofenac (1.5 mg/kg per 12 h given intramuscularly; group 2). Cumulative biliary excretion of ceftriaxone over 6 h was significantly reduced in group 2 (5,291.6 +/- 2,017.5 micrograms in group 1 versus 1,379.1 +/- 567.1 micrograms in group 2). This phenomenon occurred without any change in biliary flow. Indocyanine green clearance (20 mg/kg) increased in animals treated with ceftriaxone alone compared with the saline-treated control group (55.04 +/- 4.68 versus 33.29 +/- 7.52 ml/min per kg, respectively). Diclofenac alone caused a significant decrease in indocyanine green clearance compared with clearance in controls (25.05 +/- 4.74 versus 33.29 +/- 7.52 ml/min per kg), and indocyanine green clearance appeared not significantly different from control values in animals receiving ceftriaxone plus diclofenac. These results suggest that (i) ceftriaxone could increase hepatic blood flow and (ii) reduction of the hepatic clearance of ceftriaxone by diclofenac may be due to hepatic hemodynamic variations involving diclofenac inhibition of prostaglandin synthesis, although an interaction of diclofenac with hepatic uptake of ceftriaxone cannot be ruled out.

Animals↗

PubMed1993

Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients.

We compared cefonicid (2 g every 12 h) and ceftriaxone (2 g every 24 h) for their efficacy and safety in treating spontaneous bacterial peritonitis in cirrhotic patients in an open randomized clinical trial (30 patients in each group). Clinical, laboratory, and bacteriologic characteristics were similar in both groups. Ceftriaxone-susceptible strains were isolated on 44 occasions (94%), and cefonicid-susceptible strains were isolated on 43 occasions (91.5%). The antibiotic concentration in ascitic fluid/MIC ratio for ceftriaxone was > 100 throughout the dose interval (24 h), while it was lower for cefonicid (between 1 and 18). A total of 100% of patients treated with ceftriaxone, and 94% of those treated with cefonicid were cured of their infections (P was not significant). Hospitalization mortality was 37% in the cefonicid group and 30% in the ceftriaxone group (P was not significant). The time that elapsed between the initiation of treatment and the patient's death was shorter in the cefonicid group patients (5.3 +/- 3.90 days) than in the ceftriaxone group patients (11.8 +/- 9.15 days) (P < 0.05). None of the patients presented with superinfections, and only two patients treated with cefonicid and three patients treated with ceftriaxone developed colonizations with Enterococcus faecalis or Candida albicans. Ceftriaxone and cefonicid are safe and useful agents for treating cirrhotic spontaneous bacterial peritonitis, although the pharmacokinetic characteristics of ceftriaxone seem to be more advantageous than those of cefonicid.

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