Healio
Healio
Issue: October 2010
ByKimberly Boeser, PharmD, MPH, BCIDP
October 01, 2010
5 min read
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A closer look at a new ketolide

Issue: October 2010
ByKimberly Boeser, PharmD, MPH, BCIDP

Community-acquired pneumonia (CAP) has not recently been in the forefront of life-threatening infectious disease discussions. Even so, CAP with influenza continues to be the seventh leading cause of death in the United States. CAP affects 5 to 6 million people and costs more than $8 billion every year.

Major organizations such as the American Thoracic Society (ATS), and the IDSA issued guidelines, and the Centers for Medicare & Medicaid, the Department of Veterans Affairs, and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) still make management of CAP a priority for quality indicators.

Streptococcus pneumonia, Haemophilus influenzae and Moraxella catarrhalis are the leading pathogens associated with outpatient CAP. Less common pathogens associated with CAP are Streptococcus pyogenes,

Neisseria meningitidis, Pasteurella multocida an d atypical pathogens such as Mycobacterium pneumoniae, Chlamydia pneumoniae, and Legionella species. These may be less common pathogens but still are important when choosing an appropriate antibiotic.

Drug resistance is proving to be an issue for pathogens associated with CAP. Multi-drug resistant S. pneumoniae and H. influenzae are emerging, making CAP more difficult to treat.

In addition, mortality continues to be problematic even after the development of extended-spectrum penicillins, fluoroquinolones and macrolide antibiotics. Resistance to some of the first-line agents such as penicillins/oral cephalosporins, macrolides and fluoroquinolones are reaching 20%, 40%, and 1%, respectively. New drug development will be necessary to treat many cases of CAP.

A new agent

Cethromycin is a new agent in the ketolide class of antibacterial; the new drug application (NDA) was submitted to the FDA in 2008. Telithromycin is the other agent in the same antimicrobial class and was approved by the FDA in April 2004. The phase 1 and phase 2 trials of cethromycin were conducted in collaboration with Taisho Pharmaceuticals and Abbott Laboratories.

Further development and commercialization will be licensed exclusively to Advanced Life Sciences. The FDA Anti-Infective Drugs Advisory Committee met in June 2009, and felt that cethromycin did not demonstrate efficacy for CAP. The FDA advised the company to create a special protocol assessment (SPA) using a superiority clinical trial designed to compare cethromycin to a marketed macrolide antibiotic in two clinical trials. Advanced Life Sciences has established studies to evaluate clinical cure rates of macrolide-resistant S. pneumoniae. The committee did vote in favor of the cethromycin safety profile. Restanza (cethromycin) will maintain patent until 2016.

The ketolide antibiotic structure is very similar to that of the macrolides. Macrolides, such as erythromycin and clarithromycin, are large 14-membered rings with modifications at C6 and a ketone at C9 positions. Azithromycin is a 15-membered ring with a tertiary amino group. The ketolides, like the macrolides, are 14-member rings but differ by having a keto group at C3 of the lactone ring, with an addition of quinolyl ally side chain at C6 of the lactone ring. This large, complex drug molecule possesses some unique pharmacological properties. This ketolide acts by binding to the 23s ribosomal RNA of the 50s ribosomal subunit of the bacterial ribosome, ultimately causing dissociation of peptidyl-tRNA from the ribosome. This inhibits overall protein synthesis. Cethromycin’s chemical structure also halts protein synthesis through binding and blocking the exit tunnel of the ribosome. Upon interaction with the ribosomal subunit by hydrophobic interaction with the sugar moieties, the diameter of the tunnel is affected. Cethromycin overlaps binding sites on the ribosome. This interaction at the bacterial ribosome allows for rapid association to the binding site, slower dissociation from the active site and prolonged post-antibiotic effect (PAE).

The two major mechanisms of resistance of the macrolide class of antibiotics are ribosomal modifications and drug efflux. Several other less common mechanisms such as short-resistance peptides and point mutations at the ribosomal binding site do exist for the macrolides. Whether cethromycin will be able to overcome these mechanisms is not yet clearly established.

Ketolides have remained active against most macrolide-resistant strains. S. pneumoniae’s mechanism of resistance is the macrolide-lincosamide streptogramin B (MLSB) phenotype, resulting in the expression of erythromycin ribosome methylation gene (erm). The ketolides are not considered inducers of erm genes in S. aureus, S. pneumoniae or S. pyogenes. Cethromycin appears to effectively inhibit erm A and erm B stains for S. pneumoniae. As noted by the mechanism of action, cethromycin exhibits binding to methylated ribosomes and it is postulated that at greater concentrations, cethromycin will inhibit ribosomal protein synthesis.

S. pneumoniae’s predominant mechanism of resistance continues to be drug efflux from the cells. This occurs on the 14- and 15-membered ring compounds of the macrolides. It is known as the M phenotype due to the expression of the macrolide efflux pump-mef (E) gene.

The telithromycin MIC has been shown to double at induction of the M phenotype but resistance is not inferred by the mef (E) gene for telithromycin. The hope is that cethromycin will not induce mef (E) mediated resistance, like its fellow ketolide. Cethromycin susceptibility decreases in isolates expressing either erm or mef genes, however, inhibition has still been achieved at concentrations <1 µg/ml. This may make it useful in treating some macrolide resistant pathogens.

Primary indication

The primary indication for cethromycin will be for the treatment of CAP and its causative pathogens.

Cethromycin against S. pneumoniae proves its potency compared with the other macrolides/telithromycin and erythromycin/clindamycin as MIC90 was 0.06 µg/ml, 0.25 µg/ml and 32 µg/ml, respectively. Also, cethromycin has reported the longest PAE for S. pneumoniae at > 5.6 hrs compared with the other macrolides.

Cethromycin promises excellent activity against the predominant gram-negative pathogens associated with CAP, although potency is not as great compared with the gram positive pathogens. Two studies conducted comparing azithromycin to cethromycin have conflicting results against H. influenzae. Brueggemann suggested similar activity of these two agents at MIC50 while Barry et al showed azithromycin is more active than cethromycin again H. influenzae.

The fluoroquinolones remain more active against H. influenzae than the ketolides. Within the gram-negative group, cethromycin demonstrates more activity again M. catarrhalis than H. influenzae but comparable activity to macrolides and fluoroquinolones. Cethromycin displays excellent activity against the atypical pathogens, including Legionella species, Chlamydophila species, and Mycoplasma pneumoniae. The activity of cethromycin exceeds that of all comparable agents.

The pharmacokinetic studies have focused on doses of cethromycin 150 mg or 300 mg once daily for 5 days. The plasma drug concentrations (Cmax µg/ml) were 0.181 and 0.500 for 150 mg and 300 mg, respectively. Interestingly, patients’ pharmacokinetics with body mass index of 18-29 kg/m2 were evaluated and plasma drug levels did not appear to be affected by weight. The optimal distribution of cethromycin is accounted for by the significant binding at the ribosome. It is noted to distribute well into both epithelial lining fluid and alveolar cells, reaching higher concentrations in the pulmonary sites than in plasma of healthy individuals. The metabolism of cethromycin is not clearly understood. While telithromycin is eliminated by biliary excretion, renal excretion and hepatic metabolism — all to a certain extent — the metabolism of cethromycin needs further study. In vitro studies of human liver microsomes and recombinant CYP isoforms demonstrate metabolism to a primary metabolite (M-1) and two secondary metabolites. At this point, no dose adjustments will need to be made for mild-moderate hepatic impairment. Cethromycin is metabolized by CYP3A, suggesting drug-drug interactions will be significant. Cethromycin is estimated to be excreted ~10% in the urine and an anticipated dose reduction from 300 mg to 150 mg daily will need to occur in patients with severe renal impairment.

While cethromycin is still undergoing phase 3 clinical trials and is not yet commercially available, it has promise to be a new agent for the treatment of CAP.

Advanced Life Sciences has been studying the agent for the prophylactic treatment of anthrax and it is designated an orphan drug for this use by the FDA. An IV formulation is also being studied. The company hopes to create the first IV antibiotic of its class to allow for treatment of serious hospital acquired infections with the options to convert to oral formulation. The safety profile has been approved by the FDA, but further post marketing analysis will need to occur to insure the hepatoxicity that plagued telithromycin will not do the same for cethromycin.

The most impressive data are the potency of cethromycin against the CAP-associated pathogens. The ever-changing resistance patterns of pathogens, predominantly S. pneumoniae for CAP will require newer, unique agents. In a time when mortality is still very high for patients who develop CAP, alternatives will be necessary and essential for effective treatment.

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