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We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.
OBJECTIVES: Anti-inflammatory therapy with interleukin-10 (IL-10) was previously reported to reduce pulmonary inflammation and to prevent septicaemia in murine pneumococcal pneumonia treated with ceftriaxone. In the present report, we investigated the influence of pulmonary infection and IL-10 administration on the pharmacokinetics of ceftriaxone. METHODS: CD1 mice were infected with 10(7) cfu of Streptococcus pneumoniae. Treatments (intraperitoneal) with IL-10 (1 microg per mouse), ceftriaxone (20 mg/kg) or the combination of IL-10 + ceftriaxone were initiated 18 h after infection. Groups of mice were sacrificed at several time points from 5 min to 24 h after initiation of therapy. Ceftriaxone was quantified in blood and lungs using a microbiological assay. Additional groups of mice received a second dose of IL-10 at 36 h post-infection. Survival rates were recorded over 14 days. RESULTS: The clearance of ceftriaxone was significantly reduced in infected mice compared with that in non-infected animals (P < 0.01), whereas AUC, mean residence time, t(1/2) and AUC(lung)/AUC(serum) were significantly enhanced (P < 0.01, 0.01, 0.05, 0.05). Co-administration of IL-10 with ceftriaxone in infected animals further retained ceftriaxone in the bloodstream and reduced its volume of distribution at steady state and the ratio of AUC(lung)/AUC(serum). IL-10 alone did not modify significantly the pharmacokinetics of ceftriaxone in blood and lungs of non-infected animals. CONCLUSIONS: The results suggest that pulmonary infection, and therapy with IL-10, both affect the pharmacokinetics of ceftriaxone. Indeed, administration of IL-10 + ceftriaxone improved the survival rate of mice (P < 0.001 compared with therapy with ceftriaxone alone). IL-10 should be considered as an adjunctive therapy to antibiotics against severe infections.
OBJECTIVE: To explore pharmacokinetic factors underlying the poor bacteriologic eradication rate with a single 500-mg dose of ceftriaxone for streptococcal tonsillopharyngitis and to identify the minimum ceftriaxone dose required for effective treatment. METHODS: Population modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to patients' responses to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcus to achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug concentrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Streptococcus were obtained from a previous trial, in which all MICs (n = 115) were < or = 0.064 mg/L; 33.9% were susceptible at < or = 0.016 mg/L, 66.4% were susceptible at 0.032 mg/L, and 1.7% were susceptible at 0.064 mg/L. RESULTS: Mean population pharmacokinetic parameters and their variances reflected substantial variability of clearance and half-life in the target population. Tonsillar ceftriaxone protein binding was 89.1%. The proportions of 1000 simulated patients with free ceftriaxone concentrations that exceeded MICs of 0.016 mg/L, 0.032 mg/L, and 0.064 mg/L at 24 hours were 71.7%, 65.4%, and 57.2%, respectively, and at 48 hours were 41.8%, 35.8%, and 28.6%, respectively. The amount of time that free ceftriaxone concentrations need to exceed MIC to achieve bacteriologic success was estimated to be 36 hours. Using this time criterion, two 500-mg doses of ceftriaxone separated by 18 hours should achieve a bacteriologic cure rate of approximately 95%. CONCLUSIONS: Pharmacokinetic variability and high ceftriaxone tonsillar protein binding explain the high microbiologic failure rate for a single 500-mg dose of ceftriaxone in group A streptococcal tonsillopharyngitis. Monte Carlo simulation suggests that a second dose administered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate.
Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivo protein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100 mg/kg and caffeine 20 mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3-347 micrograms/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p less than 0.05) from 13.1 +/- 1.8 mg (mean +/- SD, 54.6% of total) to 15.3 +/- 1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC) was reduced from 612 to 516 micrograms hr/ml. Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUC values (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.
BACKGROUND: Ertapenem is a once-daily parenteral beta-lactam licensed in the United States in November 2001 and in Europe in May 2002. OBJECTIVE: This study compared the efficacy and safety profiles of ertapenem with those of ceftriaxone for the treatment of hospitalized adult patients with serious community-acquired pneumonia (CAP) requiring parenteral therapy. METHODS: In this prospective, double-blind (with sponsor blinding), multicenter study, adult patients with CAP were stratified by Pneumonia Severity Index (< or = 3 or > 3) and age (< or = 65 or > 65 years) and randomized (2:1) to receive IV or intramuscular (IM) ertapenem 1 g once daily or IV or IM ceftriaxone 1 g once daily. Investigators could switch patients to an oral antimicrobial agent if clinical improvement was shown after at least 3 days of parenteral therapy. RESULTS: A total of 364 patients were randomized to treatment: 239 to the ertapenem group and 125 to the ceftriaxone group. Three patients in the ertapenem group and 2 in the ceftriaxone group did not receive study therapy. Of the treated patients, 77.1% (182/236) of patients in the ertapenem group and 75.6% (93/123) in the ceftriaxone group were clinically evaluable. Among clinically evaluable patients, the mean (SD) durations of parenteral and total (parenteral plus optional oral) therapy were 5.5 (2.6) and 11.5 (2.7) days for ertapenem and 5.6 (2.8) and 11.7 (3.0) days for ceftriaxone, respectively. Streptococcus pneumoniae was the most frequently isolated pathogen in both treatment groups. Cure rates were 92.2% for clinically evaluable patients in the ertapenem group and 93.6% for those in the ceftriaxone group (95% CI for the difference, adjusted for stratum, -8.6 to 5.7), fulfilling the criteria for statistical equivalence. At completion of parenteral therapy, 94.7% of patients in the ertapenem group and 95.8% in the ceftriaxone group showed clinical improvement. Infused vein complications (ertapenem, 3.4% [8/236]; ceftriaxone, 7.3% [9/123]) and elevated transaminase levels (ertapenem, 6.3% [13/207]; ceftriaxone, 7.1% [8/113]) were the most common adverse events in both groups. CONCLUSIONS: In this study of hospitalized adult patients, ertapenem therapy, with an oral switch option, was as effective as ceftriaxone with the same oral switch option for treatment of CAP requiring initial parenteral therapy. The overall safety profiles of the 2 drugs were comparable.
Ceftriaxone was introduced into clinical practice in the USA in 1985 and was the first extended-spectrum (third-generation) cephalosporin approved for once-daily treatment of patients with Gram-positive or Gram-negative infections. Review of ceftriaxone activity is important given its continued use since the mid-1980s and reports of emerging resistance among all antimicrobial agent classes. We reviewed the activity of ceftriaxone and relevant comparative agents against five Gram-positive and 11 Gram-negative species for a 5-year period, 1996-2000, using data from The Surveillance Network (TSN) Database-USA. All MIC results were interpreted using NCCLS breakpoint criteria. Ceftriaxone resistance among isolates of Streptococcus pneumoniae (n=17219) remained essentially unchanged over the 5 years studied and in fact was lower from 1998 to 2000 (5.0-5.1%) than in 1996 (6.3%) and 1997 (6.6%). Ceftriaxone resistance (range, 5.1-6.9%) among viridans group streptococci (n=6621) varied by <2% from 1997 to 2000. Beta-lactam-resistant Streptococcus pyogenes (n=935) and group B beta-haemolytic streptococci (n=2267) were not identified in any year. Among methicillin-susceptible Staphylococcus aureus (n=39 284) ceftriaxone resistance was 0.1-0.3% per year from 1996 to 2000. Ceftriaxone resistance among Escherichia coli (n=472407; range, 0.2-0.4%), Klebsiella oxytoca (n=16231; range, 3.5-4.8%), Klebsiella pneumoniae (n=117754; range, 1.9-2.6%), Proteus mirabilis (n=67692; range, 0.2-0.3%), Morganella morganii (n=11251; range, 0.3-2.1%) and Serratia marcescens (n=26519; range, 1.6-3.8%) was low and consistent from 1996 to 2000. Resistance to ceftriaxone among Enterobacter cloacae (n=48114; range, 21.7-23.9%) was relatively high, compared with other Enterobacteriaceae, but unchanged from 1996 to 2000. Rates of resistance to ceftriaxone among Acinetobacter spp. (n=20813) increased from 24.8% in 1996 to 45.1% in 2000. All Haemophilus influenzae (n=7911) and Neisseria gonorrhoeae (n=218) were susceptible to ceftriaxone, as were 99.7% of Moraxella catarrhalis (n=312) tested in 1996 and 1997. In summary, ceftriaxone has retained its potent activity against the most commonly encountered Gram-positive and Gram-negative human pathogens despite widespread and ongoing clinical use for more than 15 years.
The purpose of this work was to evaluate the in vitro possibilities of ampicillin-ceftriaxone combinations for 10 Enterococcus faecalis strains with high-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of ampicillin plus ceftriaxone, both administered with humanlike pharmacokinetics, for the treatment of experimental endocarditis due to HLRAg E. faecalis. A reduction of 1 to 4 dilutions in MICs of ampicillin was obtained when ampicillin was combined with a fixed subinhibitory ceftriaxone concentration of 4 micrograms/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 micrograms of ampicillin alone per ml or in combination with 5, 10, 20, 40, and 60 micrograms of ceftriaxone per ml showed a > or = 2 log10 reduction in CFU per milliliter with respect to ampicillin alone and to the initial inoculum for all 10 E. faecalis strains studied. This effect was obtained for seven strains with the combination of 2 micrograms of ampicillin per ml plus 10 micrograms of ceftriaxone per ml and for six strains with 5 micrograms of ceftriaxone per ml. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of E. faecalis V48 or 10(5) CFU of E. faecalis V45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of ampicillin every 4 h, alone or combined with 2 g of ceftriaxone every 12 h. The levels in serum and the pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin or ceftriaxone in rabbits were similar to those found in humans treated with 2 g of ampicillin or ceftriaxone intravenously. Results of the therapy for experimental endocarditis caused by E. faecalis V48 or V45 showed that the residual bacterial titers in aortic valve vegetations were significantly lower in the animals treated with the combinations of ampicillin plus ceftriaxone than in those treated with ampicillin alone (P < 0.001). The combination of ampicillin and ceftriaxone showed in vitro and in vivo synergism against HLRAg E. faecalis.
In human subjects, ceftriaxone exhibits an exceptionally long elimination half-life (5.8 to 8.7 hours) and a small degree of nonlinearity in its pharmacokinetics which can be ignored in its clinical applications. Thirty-three to 67 percent of a dose is excreted in the urine as unchanged drug, and the remainder is secreted in the bile and ultimately is found in the feces as microbiologically inactive compounds. Ceftriaxone is rapidly and completely absorbed following intramuscular administration. Multiple dosing of ceftriaxone with doses ranging from 0.5 to 2 g at 12- or 24-hour intervals by intravenous and intramuscular routes resulted in 15 to 36 percent accumulation of ceftriaxone in plasma and no change in its elimination half-life. The volume of distribution and the plasma clearance of ceftriaxone in pediatric patients were threefold greater than those in adults, and ceftriaxone penetrated the inflamed meninges of infants and children with bacterial meningitis. Small changes in the pharmacokinetics of ceftriaxone in elderly subjects or patients with renal or hepatic dysfunction are such that dose adjustments should not be necessary with a ceftriaxone dosage up to 2 g per day. Ceftriaxone was not removed to any significant extent from plasma by hemodialysis. In a small percentage of patients, on dialysis, the elimination rate of ceftriaxone was significantly reduced, suggesting that plasma concentrations of ceftriaxone should be monitored in these patients to determine if dosage adjustments are necessary.
CONTEXT: Ceftriaxone, an expanded-spectrum cephalosporin, is an antimicrobial agent commonly used to treat severe Salmonella infections, especially in children. Ceftriaxone-resistant Salmonella infections have recently been reported in the United States, but the extent of the problem is unknown. OBJECTIVES: To summarize national surveillance data for ceftriaxone-resistant Salmonella infections in the United States and to describe mechanisms of resistance. DESIGN AND SETTING: Case series and laboratory evaluation of human isolates submitted to the Centers for Disease Control and Prevention from 17 state and community health departments participating in the National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria between 1996 and 1998. PATIENTS: Patients with ceftriaxone-resistant Salmonella infections between 1996 and 1998 were interviewed and isolates with decreased ceftriaxone susceptibility were further characterized. MAIN OUTCOME MEASURES: Exposures and illness outcomes, mechanisms of resistance. RESULTS: The prevalence of ceftriaxone-resistant Salmonella was 0.1% (1 of 1326) in 1996, 0.4% (5 of 1301) in 1997, and 0.5% (7 of 1466) in 1998. Ten (77%) of the 13 patients with ceftriaxone-resistant infections were aged 18 years or younger. The patients lived in 8 states (California, Colorado, Kansas, Massachusetts, Maryland, Minnesota, New York, and Oregon). Nine (82%) of 11 patients interviewed did not take antimicrobial agents and 10 (91%) did not travel outside the United States before illness onset. Twelve of the 15 Salmonella isolates with ceftriaxone minimum inhibitory concentrations of 16 microg/mL or higher were serotype Typhimurium but these isolates had different pulsed-field gel electrophoresis patterns. Thirteen of these 15 isolates collected between 1996 and 1998 were positive for a 631-base pair polymerase chain reaction product obtained by using primers specific for the ampC gene of Citrobacter freundii. CONCLUSIONS: Domestically acquired ceftriaxone-resistant Salmonella has emerged in the United States. Most ceftriaxone-resistant Salmonella isolates had similar AmpC plasmid-mediated resistance.
In a prospective randomized open study, ceftriaxone, 50 mg/kg per day, was compared with ampicillin, 100 mg/kg per day, both given for a period of 5 days, for the treatment of 40 children whose mean (+/- SD) age was 4.5 +/- 3.2 years and who had severe dysentery caused by Shigella organisms. Twenty patients were treated with ceftriaxone and 20 with ampicillin. Both drugs were initially given intravenously for a period of 1 to 2 days and were continued intramuscularly, in the case of ceftriaxone, or orally, in the patients receiving ampicillin. All Shigella organisms isolated were susceptible to ceftriaxone; 28% were resistant to ampicillin. The diarrhea persisted for a mean (+/- SD) period of 2.5 +/- 1.0 days in the ceftriaxone-treated patients versus 6.8 +/- 6.3 days in the ampicillin-treated patients (p less than 0.005). At the end of the 5 days of therapy, stool cultures for Shigella organisms were negative in 12 (60%) of the 20 patients from the ampicillin group and in all the children (100%) from the ceftriaxone group (p less than 0.001). Bacteriologic relapses were observed in eight (40%) of the patients treated with ampicillin but in none of the children treated with ceftriaxone (p less than 0.001). In instances of clinical or bacteriologic failure in the ampicillin group, retreatment was instituted in most of the cases with ceftriaxone; persistent clearing of the Shigella organisms from the stool was finally achieved after a mean (+/- SD) period of 11.75 +/- 9.4 days after therapy was started, as compared with 1.85 +/- 0.6 days in the ceftriaxone-treated patients (p less than 0.001). We conclude that in children with severe shigellosis, treatment with ceftriaxone for 5 days is effective and better than use of ampicillin for clinical cure and eradication of the Shigella organisms from the stool.
Approval of ceftriaxone for the treatment of otitis media has led to fear of selection of resistant mutants owing to widespread use. To test this, we examined the ability of sequential subcultures in sub-MICs of ceftriaxone, cefprozil and azithromycin to select resistant mutants in 12 pneumococci. Daily subculturing was performed 50 times or until mutants with raised ceftriaxone, cefprozil or azithromycin MICs were selected. Of eight ceftriaxone-susceptible parents, ceftriaxone did not select for any resistant mutants, while cefprozil selected for four mutants (MICs 2-4 mg/L after 21-50 subcultures). Among four ceftriaxone-resistant parents, subculturing in ceftriaxone selected for one stable mutant with raised ceftriaxone MIC (>16 mg/L after 21 subcultures) and subculturing in cefprozil selected for one mutant with raised cefprozil MIC (64 mg/L after 44 subcultures). Mutations were observed in pbp2x and pbp1a. Among six azithromycin-susceptible parents, subculturing in azithromycin selected for five resistant mutants (MIC 0.5-32 mg/L after 10-42 passages) and among six azithromycin-resistant strains, subculturing selected for mutants with raised azithromycin MICs in all six strains (MIC 16-32 mg/L after 4-18 passages). All azithromycin-resistant mutants derived from azithromycinsusceptible parents had mutations in domain V of 23S rRNA while all azithromycin-resistant parents and derived mutants had mefE. Single-step mutation rates among the 12 strains at the MIC ranged from 1.5 x 10(-6) to <6.2 x 10(-10) for ceftriaxone, >1.3 x 10(-5) to 8.9 x 10(-8) for cefprozil and >1.1 x 10(-6) to 6.7 x 10(-10) for azithromycin. Multi-step and single-step testing showed that ceftriaxone selected for resistant mutants less often than cefprozil and azithromycin.
OBJECTIVES: The aim of the study was to assess the in vitro and in vivo efficacy of ceftriaxone, vancomycin and rifampicin alone and combined against Streptococcus pneumoniae ATCC 51916 (MIC of ceftriaxone: 32 mg/L). METHODS: In vitro killing curves were performed with clinically achievable CSF antibiotic concentrations. In the rabbit model of pneumococcal meningitis, we studied the efficacy of and effects on inflammation of treatment with ceftriaxone 100 mg/kg/day, vancomycin 30 mg/kg/day and rifampicin 15 mg/kg/day, alone and combined, over a 26 h period. RESULTS: Time-kill curves showed that vancomycin was bactericidal, and ceftriaxone and rifampicin produced a bacteriostatic effect. An additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at subinhibitory concentrations. Emergence of resistance to rifampicin was detected both when rifampicin was studied alone and when combined with ceftriaxone or vancomycin. In the rabbit meningitis model, ceftriaxone was bacteriostatic, whereas rifampicin and vancomycin were bactericidal at 24 h. Although not synergistic, the combinations of ceftriaxone plus vancomycin or rifampicin, and vancomycin plus rifampicin, improved the efficacy of any antibiotic tested alone--all combinations were bactericidal from 6 h--and significantly decreased inflammatory parameters in CSF compared with control and ceftriaxone groups. CONCLUSION: Ceftriaxone plus vancomycin, and vancomycin plus rifampicin appeared to be effective in the therapy of experimental pneumococcal meningitis caused by highly cephalosporin-resistant strains such as ATCC 51916. Our results provide an experimental basis for using these combinations as empirical therapy for pneumococcal meningitis, regardless of the degree of cephalosporin resistance of the causative strain.
OBJECTIVE: To evaluate the patterns of ceftriaxone use in an urban pediatric emergency department (PED) and to determine if overuse exists based on published guidelines for management of febrile infants. METHODS: We conducted a retrospective study of 229 young febrile patients who received ceftriaxone between January 1 and March 31, 1995, in a large urban PED in a teaching hospital in Atlanta. Patients younger than 3 months, patients with chronic illnesses (eg, sickle cell anemia, HIV), and those who received ceftriaxone for sexually transmitted diseases were excluded. RESULTS: During the study period, ceftriaxone was administered 289 times to 229 patients (53% male) aged 3 months to 18 years. Sixty patients (26%) received ceftriaxone two or more times for the same illness. Data were stratified based on age, source of fever, temperature, leukocyte count, diagnosis of pneumonia, and visit order (initial or follow-up). At the time of their initial visit, 180 of 229 patients had an identifiable focus of infection (76 had pneumonia), but no source could be identified in the remaining 49. Based on temperature, leukocyte count, and the presence or absence of a focus, ceftriaxone use, as compared with practice guidelines, was justified in 40 of 229 (17.5%) patients, questionable in 43 of 229 (18.8%), and not justified in 146 of 229 (63.7%). For the 60 patients who received ceftriaxone more than once, its use was justified in only 13%. Results of blood cultures were positive in 3 of 229 (1.3%) patients. Ceftriaxone was justified according to published guidelines in two of these three patients, whereas one patient with pneumonia and pneumococcal bacteremia could have been treated with oral antibiotics. Overall, for the entire study population (289 encounters at initial and subsequent visit combined), ceftriaxone use was justified in 48 patients (16.6%), questionable in 49 patients (17%), and not justified in 192 patients (66.4%). CONCLUSIONS: Based on published guidelines, ceftriaxone use in the PED was not justified in the majority of cases.
Ceftriaxone is a broad spectrum parenteral cephalosporin that is eliminated through renal as well as biliary excretion. In order to characterize factors influencing the biliary excretion of ceftriaxone, and possible effects of this organic anion on biliary lipid transport, we studied six healthy volunteers before and during ceftriaxone infusion. The biliary secretion rates of cholesterol, bile acids, phospholipids and ceftriaxone were determined using a duodenal perfusion technique, and the biliary lipid composition and cholesterol saturation of stimulated hepatic bile were determined. Changes in the intestinal microflora induced by ceftriaxone treatment were also analysed. There was a three-fold interindividual variation in biliary excretion of ceftriaxone, and this was correlated with the secretion rate of bile acids (rs = 0.83, P = 0.05). During ceftriaxone infusion, the secretion rate of cholesterol was reduced by 32% (P less than 0.05), which resulted in a reduction of cholesterol saturation of bile, from 107 +/- 11 to 75 +/- 12% (SEM, P less than 0.05). The suppression of intestinal Escherichia coli and Bacteroides, and the proliferation of enterococci and lactobacilli were related to the biliary excretion of ceftriaxone. We conclude (i) that biliary excretion of ceftriaxone is of major importance for its effects on intestinal microflora, (ii) that secretion of this organic anion into bile is largely dependent on bile acid secretion, and (iii) that ceftriaxone inhibits the biliary secretion of cholesterol.