Ketolide Antibiotic Research Articles

A novel ketolide class: Synthesis and antibacterial activity of a lead compound

Synthesis and antibacterial activity of a new class of ketolide antibiotics, exemplified by the prototype GW680788X ( 1), are described. The structure of ( 1) has been elucidated by spectroscopic analysis. The good antibacterial activity shown by ( 1) in comparison with clarithromycin prompted us to consider this compound as a lead molecule for further exploration.

Cethromycin

Cethromycin [ABT 773, A-195773, Abbott-195773, A-1957730, A-195773-0] is a once-daily ketolide antibiotic that originated from Abbott Laboratories' research into next-generation compounds to the macrolide antibacterial, clarithromycin. The aim of the research programme was to maintain the positive attributes of clarithromycin and to add the property of efficacy against macrolide-resistant organisms. Cethromycin acts by binding to the 23S molecule of the 50S ribosomal subunit. Advanced Life Sciences is conducting multinational, pivotal phase III trials of cethromycin for the treatment of mild-to-moderate community-acquired pneumonia, phase II/III trials for treatment of acute bacterial sinusitis, as well as preclinical trials for the treatment of anthrax. Advanced Life Sciences plans to advance discussions with prospective commercialisation partners for cethromycin during 2006. Abbott Laboratories and Taisho Pharmaceutical entered a collaboration to develop and commercialise new macrolide antibacterials in October 1997. Each company brought its existing macrolides into the collaboration and both companies were to jointly develop novel new macrolides. Abbott was to have exclusive marketing, manfacturing and supply rights worldwide (except in Japan) to any compounds resulting from this collaboration. Taisho was to receive royalties on Abbott's sales in consideration of granted rights. In Japan, the two companies were to co-market any resulting macrolide antibacterials. This agreement extended to the development of cethromycin; however, the agreement was suspended in April 2004 and appears to have been terminated. Abbott exclusively licensed cethromycin to Advanced Life Sciences worldwide excluding Japan in December 2004. Advanced Life Sciences initiated commercial manufacturing agreements for cethromycin with DSM and Cardinal Health in May 2006. In March 2006, Advanced Life Sciences completed private placement of $US36 million from which the net proceeds will be used to advance development of cethromycin. The company plans to submit an NDA for cethromycin in 2007. In Japan, phase II trials were being conducted with Abbott's partner, Taisho Pharmaceutical. Although development in the US had been put on hold, Abbott was to continue to support product development in Japan by Taisho. However, in April 2004, Taisho and Abbott Japan decided to suspend co-development activities for cethromycin. A patent has been granted for cethromycin (US patent number 5 866 549) that expires in September 2016.

Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment

Telithromycin, a new ketolide antibiotic, has been implicated in the exacerbation or unmasking of myasthenia gravis. This retrospective study presents two clinical reports and summarizes eight other suspected cases notified to the French pharmacovigilance system, highlighting a potentially life-threatening risk of telithromycin treatment in myasthenic patients. An important common feature was that, in seven cases, symptomatology occurred within 2 hours of first telithromycin intake--notably in cases of severe exacerbation.

Ketolide Antibiotic and Severe Hepatotoxicity

Telithromycin (Ketek) is the first FDA-approved ketolide antibiotic. Although it is derived from macrolides, biochemical differences enable it to

The chinchilla microdialysis model for the study of antibiotic distribution to middle ear fluid

In cases of slow or limited penetration of an antibiotic to the site of infection such as in acute otitis media (the middle ear), plasma levels of the agent may not reflect the concentrations that are relevant in determining clinical outcome. There is a need for a model that allows prediction of the time-course of unbound, pharmacologically active drug levels in middle ear fluid (MEF). This article introduces microdialysis as a sampling tool to measure unbound antibiotic concentrations in the MEF of the chinchilla, and briefly summarizes the results of studies of MEF penetration of a cephalosporin, a macrolide, and a ketolide antibiotic using this technique. The general concurrence of preliminary results of the chinchilla studies with clinical findings suggests that the chinchilla microdialysis model may be useful in predicting efficacy in patients.

Effect of a newly developed ketolide antibiotic, telithromycin, on metabolism of theophylline and expression of cytochrome P450 in rats

The effects of a newly-developed ketolide antibiotic, telithromycin, on the metabolism of theophylline and the expression of hepatic cytochrome P450 (CYP) 1A2 and CYP3A2 were investigated in rats. Telithromycin at a high dose (100 mg/kg of body weight) was injected intraperitoneally once a day for 3 days. Twenty-four hours (day 4) after the final administration of telithromycin, theophylline (10 mg/kg) was administered intravenously. The presence of telithromycin significantly delayed the disappearance of theophylline from plasma. Parameters related to the pharmacokinetic interaction between theophylline and telithromycin were examined by noncompartmental methods. A significant decrease in the systemic clearance of theophylline was observed in the presence of telithromycin. Pretreatment with telithromycin significantly decreased the metabolic clearance of the major metabolites, 1-methyluric acid and 1,3-dimethyluric acid, with no change in the renal clearance of theophylline, suggesting that the decreased systemic clearance of theophylline by telithromycin is due to reduction of their metabolic clearance. Pretreatment with telithromycin significantly decreased the activity of 7-ethoxyresorufin O-deethylation and testosterone 6β-hydroxylation, suggesting that telithromycin decreases the activity of hepatic CYP1A2 and CYP3A2. Western blot analysis revealed that telithromycin significantly decreased the protein levels of CYP1A2 and CYP3A2 in the liver, which could explain the observed decreases in the systemic clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid. The present study suggests that telithromycin at the dose used in this study alters the pharmacokinetics and metabolism of theophylline, due to reductions in the activity and expression of hepatic CYP1A2 and CYP3A2.

Involvement of the Drug Transporters P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 in Telithromycin Transport

The present study aims to investigate the role of P glycoprotein and multidrug resistance-associated protein (Mrp2) in the transport of telithromycin, a newly developed ketolide antibiotic, in vitro and in vivo. The in vitro experiments revealed that the intracellular accumulation of telithromycin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P glycoprotein. Cyclosporine significantly increased the intracellular accumulation of telithromycin in K562/ADR cells. When telithromycin was coadministered intravenously with cyclosporine in Sprague-Dawley (SD) rats, cyclosporine significantly delayed the disappearance of telithromycin from plasma and decreased its systemic clearance to 60% of the corresponding control values. Hepatobiliary excretion experiments revealed that cyclosporine almost completely inhibited the biliary clearance of telithromycin, suggesting that telithromycin is a substrate of P glycoprotein and a potential substrate of Mrp2. Moreover, the biliary clearance of telithromycin was significantly decreased by 80% in Eisai hyperbilirubinemic mutant rats with a hereditary deficiency in Mrp2, indicating that Mrp2, as well as P glycoprotein, plays an important role in the biliary excretion of telithromycin. When the effect of telithromycin on the biliary excretion of doxorubicin, a substrate of P glycoprotein and Mrp2, was examined in SD rats, telithromycin significantly decreased the biliary clearance of doxorubicin by 80%. Results obtained from this study indicate that telithromycin is a substrate of both P glycoprotein and Mrp2, and these transporters are involved in the hepatobiliary transport of telithromycin.

Resistance to telithromycin is conferred by msr(A), msrC and msr(D) in Staphylococcus aureus

Resistance to telithromycin is conferred by msr(A), msrC and msr(D) in Staphylococcus aureus

Strategies Leading to the Synthesis of a Novel Ketolide Antibiotic

AbstractFor Abstract see ChemInform Abstract in Full Text.

Ketolide resistance in Streptococcus pyogenes correlates with the degree of rRNA dimethylation by Erm

Macrolide and ketolide antibiotics inhibit protein synthesis on the bacterial ribosome. Resistance to these antibiotics is conferred by dimethylation at 23S rRNA nucleotide A2058 within the ribosomal binding site. This form of resistance is encoded by erm dimethyltransferase genes, and is found in many pathogenic bacteria. Clinical isolates of Streptococcus pneumoniae with constitutive erm(B) and Streptococcus pyogenes with constitutive erm(A) subtype (TR) are resistant to macrolides, but remain susceptible to ketolides such as telithromycin. Paradoxically, some strains of S. pyogenes that possess an identical erm(B) gene are clinically resistant to ketolides as well as macrolides. Here we explore the molecular basis for the differences in these streptococcal strains using mass spectrometry to determine the methylation status of their rRNAs. We find a correlation between the levels of A2058-dimethylation and ketolide resistance, and dimethylation is greatest in S. pyogenes strains expressing erm(B). In constitutive erm strains that are ketolide-sensitive, appreciable proportions of the rRNA remain monomethylated. Incubation of these strains with subinhibitory amounts of the macrolide erythromycin increases the proportion of dimethylated A2058 (in a manner comparable with inducible erm strains) and reduces ketolide susceptibility. The designation 'constitutive' should thus be applied with some reservation for most streptococcal erm strains. One strain worthy of the constitutive designation is S. pyogenes isolate KuoR21, which has lost part of the regulatory region upstream of erm(B). In S. pyogenes KuoR21, nucleotide A2058 is fully dimethylated under all growth conditions, and this strain displays the highest resistance to telithromycin (MIC > 64 microg ml-1).

Telithromycin for the Treatment of Acute Bacterial Maxillary Sinusitis: A Review of a New Antibacterial Agent

Telithromycin, the first approved ketolide antibiotic, was developed to treat community-acquired respiratory tract infections, including acute bacterial maxillary sinusitis (ABMS). A previously published study showed that a 5-day course of 800 mg telithromycin once daily is as effective as a 10-day course in the treatment of ABMS. Data were pooled from two controlled, multinational, prospective, randomized, double-blinded ABMS trials comparing 5-day telithromycin (800 mg once daily) with 10-day amoxicillin-clavulanate (500/125 mg 3 times daily) and cefuroxime axetil (250 mg twice daily). Clinical cure and bacteriologic eradication rates were compared by means of descriptive statistics. The clinical cure rate for telithromycin was 80.9% versus 77.4% for comparators; bacteriologic eradication rate for telithromycin was 84.9% versus 81.7% for comparators. Most adverse events were mild to moderate in intensity and, most commonly, gastrointestinal in nature. These results support the conclusion that 5 days of treatment with telithromycin is as safe and effective in patients with ABMS as a 10-day course of treatment with amoxicillin-clavulanate or cefuroxime axetil.

9-Oxime-3-ketolides: Modification at the C-11,12-diol moiety and antibacterial activities against key respiratory pathogens

In the search for new types of ketolide antibiotics active against key respiratory pathogens including erythromycin-resistant strains, we conducted an extensive study on the modification at the C-11,12-diol moiety of 9-oxime-3-ketolide derivatives. Among the derivatives prepared, compound 6 with carbonate at the C-11,12 position was found to have potent antibacterial activities against erythromycin-resistant Staphylococcus aureus as well as other erythromycin-susceptible strains.

Telithromycin—A Ketolide Antibiotic for the Treatment of Outpatients With Community-acquired Respiratory Tract Infections

Telithromycin—A Ketolide Antibiotic for the Treatment of Outpatients With Community-acquired Respiratory Tract Infections

Telithromycin: A Ketolide Antibiotic for Treatment of Respiratory Tract Infections

Telithromycin, a recently approved ketolide antibiotic derived from 14-membered macrolides, is active against erythromycin-resistant pneumococci. Telithromycin has enhanced activity in vitro because it binds not only to domain V of ribosomal RNA (like macrolides do) but also to domain II. However, it is not active against streptococci and staphylococci with constitutive macrolide, lincosamide, and streptogramin B resistance. Telithromycin, available in an oral formulation, is approved by the US Food and Drug Administration for use in adults for treatment of (1) community-acquired pneumonia due to Streptococcus pneumoniae (including multidrug-resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae; (2) acute exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, or M. catarrhalis; or (3) acute bacterial sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, or methicillin- and erythromycin-susceptible Streptococcus aureus. It is not approved for treatment of tonsillitis, pharyngitis, or severe pneumococcal pneumonia. Unique visual adverse effects occurred in 0.27%-2.1% of patients receiving telithromycin therapy. Its enhanced activity against some common respiratory pathogens makes it a valuable addition to the available macrolides.

An efficient entry to new sugar modified ketolide antibiotics

A new and efficient route to a ketolide aglycon served as a basis for the unprecedented 5- O-glyco-modification of ketolide antibiotics. Combined with an effective copper-catalyzed triazole-forming reaction a series of novel and potent ketolide antibiotics were synthesized.

Synthesis and Antibacterial Activity of C‐6 Carbamate Ketolides, a Novel Series of Orally Active Ketolide Antibiotics.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An examination of the differential sensitivity to ketolide antibiotics in ermB strains of Streptococcus pyogenes and Streptococcus pneumoniae.

Several reports in the literature have described a differential sensitivity to ketolide antibiotics in ermB strains of Streptococcus pyogenes and Streptococcus pneumoniae resistant to erythromycin. Strains of S. pyogenes and S. pneumoniae carrying different erm gene alleles were examined for their susceptibility to the ketolide antibiotics cethromycin (ABT-773) and telithromycin. The effect of the antibiotics on cell growth and viability was assessed as were effects on protein synthesis and 50S ribosomal subunit formation. The susceptibility of wild-type strains of both organisms was compared with effects in strains containing the ermA and ermB methyltransferase genes. A wild-type antibiotic-susceptible strain of S. pyogenes was comparable to an ermA strain of the organism in its ketolide sensitivity, with IC(50) values for 50% inhibition of protein synthesis and 50S ribosomal subunit formation of 10 ng/mL for cethromycin and 16 ng/mL for telithromycin. An S. pneumoniae strain with the ermB gene and an S. pyogenes strain with the ermA gene were also similar in their sensitivity to ketolide inhibition. IC(50) values for inhibition of translation and subunit formation in S. pneumoniae ( ermB) were 30 ng/mL and 55 ng/mL and for the ermA strain of S. pyogenes they were 15 ng/mL and 35 ng/mL respectively. By contrast, an S. pyogenes ermB strain was significantly more resistant to both ketolides, with IC(50) values for inhibition of 50S synthesis of 215 and 380 ng/mL for the two ketolides. Experiments were conducted to examine ribosome synthesis and translational activity in the two ermB strains at intervals during growth in the presence of each antibiotic. Cell viability and 50S subunit formation were dramatically reduced in the S. pneumoniae strain during continued growth with either drug. By contrast, the ketolides had little effect on the S. pyogenes strain growing with the antibiotics. The results indicate that ketolides have a reduced inhibitory effect on translation and 50S subunit synthesis in S. pyogenes with the ermB gene compared with the other strains examined.

Telithromycin treatment of chronic Chlamydia pneumoniae infection in C57BL/6J mice.

Chronic Chlamydia pneumoniae infections have been associated with atherosclerosis, but clear knowledge about how these infections should be treated is lacking. We studied the effect of a new ketolide antibiotic, telithromycin, on chronic C. pneumoniae lung infection. Female C57BL/6J mice on a 0.2% cholesterol diet were inoculated intranasally with C. pneumoniae either two or three times every fourth week. Telithromycin was given to the mice subcutaneously at 75 mg/kg of body weight once daily for 5 or 10 days, starting at 3 days after the last inoculation. Samples were taken at 4 and 12 weeks after the last inoculation. The presence of C. pneumoniae DNA in lung tissue was demonstrated by PCR and the detection of lipid accumulation in the aortic sinus by Oil-Red-O staining. C. pneumoniae DNA positivity and inflammatory reactions in the lung tissue of the mice inoculated twice were significantly affected by treatment after both inoculations or only after the second inoculation at 12 weeks. Intimal lipid accumulation in the aortic sinus was also slightly but significantly less abundant in the mice treated after both inoculations compared to the levels in those treated only after the second inoculation for 10 days (geometric means, 823 and 4,324 microm(2), respectively; P = 0.033). No differences between the infected, untreated controls and the group inoculated three times and treated for 5 days were seen. We conclude that telithromycin is effective in preventing the development of chronic C. pneumoniae infection and intimal lipid accumulation in C56BL/6J mice when the treatment is given after each inoculation.

Telithromycin-induced acute interstitial nephritis: A first case report

Telithromycin, a ketolide antibiotic used for the treatment of community-acquired respiratory infections, is widely prescribed in primary care practice. Treatment-related adverse events are mainly of gastrointestinal origin and generally mild in intensity. The authors report the first case of telithromycin-induced severe acute interstitial nephritis. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure.

Impact of cethromycin (ABT-773) therapy on microbiological, histologic, immunologic, and respiratory indices in a murine model of Mycoplasma pneumoniae lower respiratory infection.

Mycoplasma pneumoniae is a major etiologic agent of acute lower respiratory infections. We evaluated the antimicrobial and immunologic effects of cethromycin (ABT-773), a ketolide antibiotic, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were inoculated intranasally once with 10(6) CFU of M. pneumoniae on day 0. Treatment was started 24 h after inoculation. Groups of mice were treated subcutaneously with cethromycin at 25 mg/kg of body weight or with placebo daily until sacrifice. Five to ten mice per group were evaluated at days 1, 4, 7, and 10 after inoculation. Outcome variables included bronchoalveolar lavage (BAL) for M. pneumoniae quantitative culture and cytokine and chemokine concentration determinations by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], interleukin-1beta [IL-1beta], IL-2, IL-4, IL-12, granulocyte-macrophage colony-stimulating factor, IL-8, monocyte chemoattractant protein 1 [MCP-1], and macrophage inflammatory protein 1alpha [MIP-1alpha]), histopathologic score of the lungs (HPS), and pulmonary function tests (PFT) using whole-body, unrestrained plethysmography at the baseline and post-methacholine exposure as indicators of airway obstruction (AO) and airway hyperresponsiveness (AHR), respectively. The cethromycin-treated mice had a greater reduction in M. pneumoniae culture titers than placebo-treated mice, reaching statistical significance on days 7 and 10 (P < 0.05). HPS was significantly reduced in cethromycin-treated mice compared with placebo-treated mice on days 4, 7, and 10 (P < 0.05). Cytokine concentrations in BAL samples were reduced in mice that received cethromycin, and the differences were statistically significant for 7 of the 10 cytokines measured (TNF-alpha, IFN-gamma, IL-1beta, IL-8, IL-12, MCP-1, and MIP-1alpha) on day 4 (P < 0.05). PFT values were improved in the cethromycin-treated mice, with AO and AHR significantly reduced on day 4 (P < 0.05). In this mouse model, treatment with cethromycin significantly reduced M. pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR.