Ketolide Antimicrobial Agent Research Articles

Aerosol-based efficient delivery of telithromycin, a ketolide antimicrobial agent, to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections

Purpose: The efficacy of aerosol-based delivery of telithromycin (TEL), as a model antimicrobial agent, for the treatment of respiratory infections was evaluated by comparison with oral administration. Method: The aerosol formulation (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer®. Results and discussion: The time courses of the concentration of TEL in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) following administration of an aerosol formulation to rat lungs were markedly higher than that following the administration of an oral formulation (50 mg/kg). The time course of the concentrations of TEL in plasma following administration of the aerosol formulation was markedly lower than that in ELF and AMs. These results indicate that the aerosol formulation is more effective in delivering TEL to ELF and AMs, compared to the oral formulation, despite a low dose and it avoids distribution of TEL to the blood. In addition, the antibacterial effects of TEL in ELF and AMs following administration of the aerosol formulation were estimated by pharmacokinetics/pharmacodynamics analysis. The concentrations of TEL in ELF and the AMs time curve/minimum inhibitory concentration of TEL ratio were markedly higher than the effective values. Conclusion: This study indicates that an antibiotic aerosol formulation may be an effective pulmonary drug delivery system for the treatment of respiratory infections.

Pharmacokinetics of ABT-773, a new semi-synthetic ketolide in neutropenic lung-infected mice: a population approach.

ABT-773 is an investigational ketolide antimicrobial agent with an in-vitro bactericidal activity against macrolide-susceptible and -resistant Streptococcus pneumoniae. The pharmacokinetics of this drug candidate were evaluated in lung-infected (108 CFU mL 1 starting inoculum) mice following a single dose (25, 50, 100 or 200 mg kg(-1)) oral administration as a solution in 10% of 95% ethanol and 90% of 0.1 M pH 6.5 phosphate buffer solution. Serum ABT-773 concentrations were measured using a validated HPLC assay with fluorescence detection (excitation at 324 nm and emission at 364 nm). Population pharmacokinetic analysis was performed using the NONMEM computer program. Results from data analysis showed non-linear pharmacokinetics of ABT-773, noted by the increases in half-life (3.1 to 27.2 h) and AUC/dose (23.7 to 149 mg h(-1) L(-1) mg(-1)), with doses from 25 to 200 mg kg(-1). A non-linear one-compartment model with parallel capacity-limited and linear first-order elimination best described the pharmacokinetics of ABT-773 in the mouse. The total volume of distribution was 0.316 L. The clearance for the linear first-order elimination was 0.0027 L h(-1). The Vm and Km were 0.0385 L h(-1) and 0.141 mg L(-1), respectively, for the capacity-limited elimination.

Distribution Characteristics of Telithromycin, a Novel Ketolide Antimicrobial Agent Applied for Treatment of Respiratory Infection, in Lung Epithelial Lining Fluid and Alveolar Macrophages

The distribution characteristics of telithromycin (TEL), a novel ketolide antimicrobial agent, in lung epithelial fluid (ELF) and alveolar macrophages (AMs) were evaluated. In vivo animal experiments, the time-courses of the concentrations of TEL in ELF and AMs following oral administration of TEL solution (50 mg/4 mL/kg) to rats were markedly higher than in plasma, and areas under drug concentration-time curve (AUC) ratios of ELF/plasma and AMs/plasma were 2.4 and 65.3, respectively. In vitro transport experiments, the basolateral-to-apical transport of TEL through model lung epithelial cell (Calu-3) monolayers was greater than apical-to-basolateral transport. Rhodamine123 and verapamil, MDR1 substrates, reduced the basolateral-to-apical transport of TEL. In vitro uptake experiments, the intracellular equilibrated concentration of TEL in cultured AMs (NR8383) was approximately 40 times the extracellular concentration. The uptake of TEL by NR8383 was inhibited by rotenone and FCCP, ATP depletors and was temperature-dependent. These data suggest that the high distribution of TEL to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by AMs themselves via active transport mechanisms.

Apparent anaphylactoid reaction after treatment with a single dose of telithromycin

Telithromycin, the first ketolide antimicrobial agent available in the United States, is related to the macrolide class of antibiotics. Reports of immediate-type hypersensitivity reactions with macrolides or ketolides are rare overall. To describe a patient with a severe, apparent mast cell-mediated reaction to telithromycin. A 54-year-old woman with a history of hypertension was prescribed telithromycin by her primary care physician for presumed bacterial sinusitis. Shortly after ingesting the first dose of telithromycin she developed severe shortness of breath, wheezing, and angioedema. Her allergic history was significant for the development of a maculopapular rash after taking sulfonamide antibiotics, but she had received erythromycin and azithromycin in the past with no adverse effects. She was intubated with difficulty and was treated with epinephrine, diphenhydramine, and corticosteroids. The patient made a full recovery. Although not confirmed, the patient's severe symptoms were anaphylactoid and were ascribed to an immediate-type hypersensitivity reaction to telithromycin. No other causative agents, including other drugs, foods, and environmental exposures, were implicated in this case. Her history of tolerability to macrolide antibiotics is of interest considering the chemical similarities between these drugs and telithromycin. To our knowledge, this is the first reported case of a severe, immediate-type hypersensitivity reaction to telithromycin. Physicians prescribing this drug should be aware of this rare but serious effect.

Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model

Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (≥65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in log CFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45–146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5–3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.

Intrapulmonary Pharmacokinetics of Telithromycin, a New Ketolide, in Healthy Japanese Volunteers

The concentrations of telithromycin, a new ketolide antimicrobial agent, in alveolar macrophages (AMs) and bronchoalveolar epithelial lining fluid (ELF) were determined in order to investigate the transfer of the drug into target tissue, relative to plasma, following multiple oral doses of telithromycin. Twenty-four healthy male Japanese volunteers were randomly allocated to four groups. Each subject was given 600 or 800 mg of telithromycin once daily for 5 days, followed by bronchoalveolar lavage (BAL) 2 or 8 h after the last dose (group A and B: 600 mg, 2 and 8 h BAL time point; group C and D: 800 mg, 2 and 8 h BAL time point). The mean concentrations of the drug in AMs and ELF were 34.54 and 4.92 mg/liter in group A, 50.97 and 2.26 mg/liter in group B, 25.47 and 4.24 mg/liter in group C, and 108.22 and 4.31 mg/liter in group D, respectively, which markedly exceeded concentrations in plasma. These results demonstrated good transfer of telithromycin into AMs and ELF, suggesting good efficacy against common respiratory pathogens, including intracellular pathogens and atypical microorganisms.

The in vitro activity of ABT773, a new ketolide antimicrobial agent.

The in vitro activity of ABT773, a ketolide antimicrobial agent, was investigated and compared with those of seven other antibiotics. Type strains and 733 Gram-positive, Gram-negative and anaerobic isolates of clinical origin and four CHLAMYDIA: isolates were used. The activity of ABT773 was very similar to that of telithromycin, the other ketolide tested. The MIC(90) was < or = 0.5 mg/L for all bacteria examined except methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae and BACTEROIDES: spp. The antichlamydial activity of ABT773 was greater than that of telithromycin, erythromycin and ciprofloxacin. Neither an increase in the size of the inoculm nor the addition of human serum had any marked affect on the in vitro activity of ABT773.

Determination of MIC Quality Control Ranges for ABT-733, a Novel Ketolide Antimicrobial Agent

Determination of MIC Quality Control Ranges for ABT-733, a Novel Ketolide Antimicrobial Agent

Determination of MIC Quality Control Ranges for ABT-733, a Novel Ketolide Antimicrobial Agent

Determination of MIC Quality Control Ranges for ABT-733, a Novel Ketolide Antimicrobial Agent

The ketolide antimicrobial agent HMR-3004 inhibits neutrophil superoxide production by a membrane-stabilizing mechanism

We have investigated the membrane-stabilizing potential of the prototype ketolide antimicrobial agent, HMR-3004 (3.75–125 μM), as well as the effects of this agent on the production of superoxide by human neutrophils activated with FMLP, the calcium ionophore A23187, phorbol 12-myristate 13-acetate (PMA) or opsonized zymosan (OZ), each of which uses different transductional mechanisms to activate NADPH-oxidase. Membrane-stabilizing activity was investigated using a hemolytic procedure, while superoxide production was assayed by lucigenin-enhanced chemiluminescence. At concentrations of 3.75 μM and greater, HMR-3004 caused dose-related inhibition of superoxide production by neutrophils activated by all four stimuli of membrane-associated oxidative metabolism, which was not associated with cytotoxicity or superoxide-scavenging activity. At the same concentrations, HMR-3004 antagonized the hemolytic actions of the membrane-disruptive bioactive phospholipids, lysophosphatidylcholine (LPC), platelet-activating factor (PAF) and lyso-PAF. A mechanistic relationship between the membrane-stabilizing and the anti-oxidative properties of HMR-3004 was suggested by the observation that treatment of neutrophils with non-cytolytic concentrations of LPC antagonized the inhibitory effects of the ketolide on superoxide production by these cells. These membrane-stabilizing, anti-oxidative activities of HMR-3004 suggest that in addition to its antimicrobial properties, this agent possesses anti-inflammatory properties which are superior to those of the presently available macrolide and azalide agents.