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

Beskid, G.; Christenson, James G.; Cleeland, Roy; DeLorenzo, W. F.; Trown, P. W.

doi:10.1128/aac.20.2.159

Cited by 41 publications

(19 citation statements)

References 16 publications

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“…Previous studies have proven the superiority of ceftriaxone (beta-lactam antibiotic) over other antibiotics in various infections (20)(21)(22). Inclusion of sulbactam (beta lactamase inhibitor) and disodium EDTA with ceftriaxone further enhances the antibacterial spectrum against difficult-to-treat ESBL-/MBL-positive infections, due to synergistic effect of the FDC, yielding better clinical outcomes (23,24).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

et al. 2015

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ABSTRACT. Increased antibacterial resistance (ABR) and limited drug discovery warrant optimized use of available antibiotics. One option is to rationally combine two antibiotics (fixed dose combination (FDC)) that may delay or prevent emergence of ABR in notorious pathogen. Major concern with FDC is the mutual interaction of its components that might influence their pharmacokinetic (PK) profile, requiring reassessing of whole formulation (adding cost and time). The interaction can be identified by comparing PK profile of a drug present in FDC with its independent entity. An open-label, crossover, single-dose comparative PK study of FDC (ceftriaxone and sulbactam) with their individual reference formulations was performed in 24 healthy adult subjects. No mutual PK interactions between ceftriaxone and sulbactam were observed. Pharmacokinetic data was used to develop a population-PK model to understand between-subject variability (BSV). Pharmacokinetics of ceftriaxone/sulbactam was explained by one and two compartment models, respectively. The subject's Bweight^was identified as a covariate explaining BSV. Both internal and external validations (healthy/infected subjects) were done. The modelderived population-PK parameters of FDC's active components in infected subjects were similar to literature reported values of individual components. Efficacies of various FDC dosage regimens over a range of minimum inhibitory concentrations (MICs) were assessed by Monte Carlo simulations using population-PK parameters of infected/healthy subjects. In infected subjects, 3 g FDC/24 h can treat bacteria with MIC ≤8 μg/mL, while for MIC 8-32 μg/mL, 3 g FDC/12 h is recommended. Lastly, the developed population-PK model was successfully used to predict drug exposure in pediatric population.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

et al. 2015

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“…It has been established that in both healthy subjects and most patients, the mean half-life of CRO in serum is approximately 8 h (8,9,33). CRO exhibits a broad spectrum of antimicrobial activity, including common respiratory pathogens (e.g., Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and members of the family Enterobacteriaceae) (1,6,8,10,11,15).…”

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confidence: 99%

“…Ceftriaxone (CRO) is a cephalosporin characterized by a very broad spectrum of activity (1,6,8,10) and especially by an extraordinarily long elimination half-life in serum, which is an unusual pharmacological property for this class of antibiotics (5,8,30,33). It has been established that in both healthy subjects and most patients, the mean half-life of CRO in serum is approximately 8 h (8,9,33).…”

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confidence: 99%

In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model

Moine

Vallée

Azoulay-Dupuis

et al. 1994

Antimicrob Agents Chemother

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The increasing emergence of penicillin-resistant (P') strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (PS) strain (MICs of <0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the PS strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the pr strain, whereas 20-and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the PS strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [AtMIC], .8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: AtMIC, <2 h; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

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“…First, we determined the dose of each antibiotic that produced, after a single subcutaneous injection in mice, plasmatic peak concentrations that corresponded to human concentrations, according to literature and our pilot experiments: 200 mg/kg for FOX (1), 70 mg/kg for CRO (5), and 100 mg/kg for IMP (24) and ETP (12). Then, single-dose pharmacokinetic studies were performed after a single subcutaneous injection in mice for these selected doses.…”

Section: Methodsmentioning

confidence: 99%

Cefoxitin as an Alternative to Carbapenems in a Murine Model of Urinary Tract Infection Due to Escherichia coli Harboring CTX-M-15-Type Extended-Spectrum β-Lactamase

Lepeule

Ruppé

Lê

et al. 2012

Antimicrob Agents Chemother

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We investigated the efficiency of the cephamycin cefoxitin as an alternative to carbapenems for the treatment of urinary tract infections (UTIs) due to Escherichia coli producing CTX-M-type extended-spectrum ␤-lactamases. The susceptible, UTIinducing E. coli CFT073-RR strain and its transconjugant CFT073-RR Tc (pbla CTX-M-15 ), harboring a bla CTX-M-15 carryingplasmid, were used for all experiments. MICs of cefoxitin (FOX), ceftriaxone (CRO), imipenem (IMP), and ertapenem (ETP) for CFT073-RR and CFT073-RR Tc (pbla CTX-M-15 ) were 4 and 4, 0.125 and 512, 0.5 and 0.5, and 0.016 and 0.032 g/ml, respectively. Bactericidal activity was similarly achieved in vitro against the two strains after 3 h of exposure to concentrations of FOX, IMI, and ETP that were 2 times the MIC, whereas CRO was not bactericidal against CFT073-RR Tc (pbla CTX-M-15 ). The frequencies of spontaneous mutants of the 2 strains were not higher for FOX than for IMP or ETP. In the murine model of UTIs, mice infected for 5 days were treated over 24 h. Therapeutic regimens in mice (200 mg/kg of body weight every 3 h or 4 h for FOX, 70 mg/kg every 6 h for CRO, 100 mg/kg every 2 h for IMP, and 100 mg/kg every 4 h for ETP) were chosen in order to reproduce the percentage of time that free-drug concentrations above the MIC are obtained in humans with standard regimens. All antibiotic regimens produced a significant reduction in bacterial counts (greater than 2 log 10 CFU) in kidneys and bladders for both strains (P < 0.001) without selecting resistant mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla CTX-M-15 ) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli. Over the last decade, resistance to ␤-lactams among Enterobacteriaceae has emerged as a major public health threat. This is mostly due to proliferation of extended-spectrum ␤-lactamases (ESBLs), especially of the CTX-M-type, which have spread worldwide both in hospitals and the community (9). Escherichia coli isolates that produce CTX-M (especially CTX-M-15 in Western countries) are currently a serious cause of urinary tract infections (UTIs) in the community (36). Mortality in the most severe infections, particularly those evolving into bacteremia, is as high as 60% (27). In addition, associated resistance to other classes of antimicrobial agents is often observed in CTX-M producers, limiting the availability of therapeutic options. Carbapenems are widely regarded as the drug of choice for parenchymal infections due to ESBL-producing Enterobacteriaceae (35). However, several reports have described the emergence of resistance to carbapenems in Enterobacteriaceae by two mechanisms: (i) in vivo selection of porin-deficient mutants under therapy with carbapenems (11,20) and (ii) emergence of carbapenemases, reported extensively in Klebsiella pneumoniae (18, 30) and more recently in E. coli (18,29). The rise of ESBLs h...

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

Cited by 41 publications

References 16 publications

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model

Cefoxitin as an Alternative to Carbapenems in a Murine Model of Urinary Tract Infection Due to Escherichia coli Harboring CTX-M-15-Type Extended-Spectrum β-Lactamase

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