Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant

Related Experiment Video

Updated: Oct 31, 2026

Assay Development for High-Throughput Drug Screening Against Mycobacteria
07:50

Assay Development for High-Throughput Drug Screening Against Mycobacteria

Published on: October 25, 2024

I Lutsar1, A Ahmed, I R Friedland

  • 1Department of Pediatrics, Southwestern Medical Center, Dallas, Texas 75235-9063, USA.

Antimicrobial Agents and Chemotherapy
|November 26, 1997
PubMed

Insights

Achieving effective beta-lactam antibiotic levels in cerebrospinal fluid (CSF) is crucial for treating resistant pneumococcal meningitis. Ceftriaxone

Area of Science:

  • Pharmacology
  • Infectious Diseases
  • Microbiology

Background:

  • Meningitis caused by drug-resistant Streptococcus pneumoniae presents challenges in achieving adequate beta-lactam antibiotic concentrations in cerebrospinal fluid (CSF).
  • High cephalosporin resistance in S. pneumoniae necessitates optimized antibiotic dosing strategies.

Purpose of the Study:

  • To evaluate the efficacy of ceftriaxone in treating experimental pneumococcal meningitis with high cephalosporin resistance.
  • To determine the pharmacokinetic-pharmacodynamic (PK-PD) targets for ceftriaxone in CSF and their correlation with bacterial killing.

Main Methods:

  • Experimental model of highly cephalosporin-resistant pneumococcal meningitis.
  • Administration of ceftriaxone at 150 or 400 mg/kg/day in one or two doses.
  • Measurement of bacterial killing rate and PK-PD indices, including T>MBC (time above minimum bactericidal concentration).

Main Results:

  • T>MBC in CSF was the sole independent predictor of the bacterial killing rate (r = 0.87; P = 0.004).
  • CSF sterilization was achieved only when T>MBC reached 95-100%.
  • A higher T>MBC and bacterial killing rate were observed with a 200 mg/kg/12h regimen compared to 400 mg/kg/24h in the initial 24 hours.

Conclusions:

  • Ceftriaxone's bactericidal activity against resistant S. pneumoniae is time-dependent, with T>MBC being a critical PK-PD target.
  • Optimizing dosing frequency to maximize T>MBC is essential for achieving CSF sterilization in pneumococcal meningitis.
  • Twice-daily dosing of ceftriaxone demonstrated superior early bacterial killing compared to once-daily dosing.

Related Concept Videos

Mechanism of Antibiotic Resistance in MRSA01:25

Mechanism of Antibiotic Resistance in MRSA

Antibiotic resistance in bacteria arises when microorganisms evolve the ability to withstand drugs designed to kill them or inhibit their growth, rendering once-effective treatments useless. This phenomenon, driven by genetic change and selection under antibiotic exposure, poses a profound threat to modern medicine. Mechanisms include drug-inactivating enzymes (e.g., β-lactamases), efflux pumps that eject antibiotics, mutations altering antibiotic targets, decreased drug uptake, and acquisition...
Bacterial Meningitis II: Pathophysiology01:26

Bacterial Meningitis II: Pathophysiology

Bacterial meningitis typically begins when pathogens such as Neisseria meningitidis and Streptococcus pneumoniae colonize the nasopharynx and invade the bloodstream. This process is facilitated by bacterial virulence factors, such as polysaccharide capsules, which resist phagocytosis and complement-mediated killing. Less commonly, bacteria reach the central nervous system via contiguous spread from infections like otitis media or sinusitis, through congenital or acquired dural defects, or...
Clinical Significance of Antibiotic Resistance01:25

Clinical Significance of Antibiotic Resistance

Methicillin-resistant Staphylococcus aureus (MRSA) presents a critical public health threat, arising from its capacity to resist β-lactam antibiotics due to acquisition of the mecA gene within the staphylococcal cassette chromosome mec (SCCmec). This gene encodes penicillin-binding protein 2a (PBP2a), which impairs binding efficacy of methicillin and other β-lactams. MRSA has evolved into distinct clonal lineages impacting humans and animals alike, reinforcing its significance within the One...
Inhibitors of Gram-positive Cell Wall Synthesis01:23

Inhibitors of Gram-positive Cell Wall Synthesis

Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence01:22

Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence

Generic intravenous (IV) drugs are considered bioequivalent to their branded counterparts due to their 100% bioavailability upon administration. However, variations in stability among different drug products can significantly influence their therapeutic performance, even if they are pharmaceutically equivalent.Cefuroxime, a prophylactic antimicrobial, is often used as a single-dose IV injection for patients undergoing coronary artery bypass grafting surgery. A 3 g dose typically provides...
Combined Effects of Drugs: Synergism01:27

Combined Effects of Drugs: Synergism

Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
Such synergistic combinations...