Tag: medicine

Ceftobriprole medocaril – background, FDA approval and antibiotic prodrugs

Mark Butler and David Paterson

Background. Ceftobiprole medocaril (Zevtera®) has recently been in the news as Basilea Pharmaceutica was granted approval for Zevtera® by US FDA on April 2024 for treatment of adult patients with (1) methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) bacteraemia, including right-sided infective endocarditis, (2) acute bacterial skin and skin structure infections (ABSSSI) and (3) community acquired bacterial pneumonia (CABP). The structure of ceftobiprole (BAL 9141, Ro 63-9141) was first disclosed in a 1999 patent from Hoffmann La Roche and its prodrug ceftobiprole medocaril in 2001 (Fig. 1). Ceftobiprole has in vitro antimicrobial activity against a broad range of Gram-positive and Gram-negative pathogens. Notably this includes MRSA which is highly unusual for a cephalosporin. Ceftobiprole has a much higher affinity for PBP-2a than first, second, third and fourth generation cephalosporins.

Persistence Pays Off in the End. The development of Zevtera® has been a long time coming, with a number of clinical development roadblocks encountered along the way. Pivotal trials for complicated skin and skin structure infections (cSSSI), CABP, hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) were conducted at more than 150 sites from 2005 to 2007 in a collaboration between Basilea and J&J. Neither FDA nor EMA approval was granted at that time because of regulatory concerns related to clinical trial conduct at some trial sites. This led to a lawsuit against J&J, with a Dutch court eventually awarding Basilea $130 million for breach of the licence agreement. As a result, Basilea took total control of subsequent clinical trials – an ABSSSI trial was repeated and a landmark trial of ceftobiprole for complicated S. aureus bloodstream infections. It is these trials that led to the recent US FDA approval. Zevtera® has been previously approved in Canada and 14 European countries from 2013 with future expansion plans.

Medocaril/Medoxomil Antibiotic Prodrugs. Zevtera® is administered intravenously (IV) as the prodrug as ceftobiprole has low water solubility at physiological pH. Ceftobiprole medocaril is rapidly hydrolysed by plasma esterases and transported around the body. The related medoxomil prodrug moiety is present in lenampicillin and faropenem medoxomil (Fig. 2). This prodrug strategy is subtly different to using a prodrug to enhance oral dosing (e.g. contezolid acefosamil, Fig. 2).

The carbamate containing medocaril and carbonate containing medoxomil prodrugs metabolise to give the drug, diacetyl (food flavour!) and carbon dioxide (CO2) – see a metabolism study for olmesartan medoxomil, which is an angiotensin II type 1 receptor antagonist used for antihypertension (Fig. 3). Bioactivation of this type of prodrug is due to esterase enzymes such as carboxylesterases, cholinesterases, and paraoxonases, which are widely distributed in biological fluids and tissues found throughout the body.

Tetracycline has left its (fluorescent) mark on the world

Evidence of tetracycline containing fermentations in northern Africa around 1,500 years ago.

This is some older research published in 2010 (available here) that I recently read, which I wanted to share.

Some bones excavated from northern Africa (modern day Egypt and Sudan) burials have bright yellow-green fluorescent bands (λ 490 nm), which was similar to those observed in people treated with first generation tetracycline antibiotics. When first found, fluorescent bands were conjectured to have formed post death or through infection. More on the history of tetracycline (ancient uses and its rediscovery) can be found in this lecture text (available here).

Bones from a four-year-old Nubian child buried around 1,500 years ago were demineralised with hydrofluoric acid (HF) to release the fluorescent compound(s) (available here). HPLC-MS analysis showed two closely eluting peaks with a m/z of 427.1 Da. Authentic standards were derived from HF treatment of tetracycline, oxytetracycline and chlortetracycline, which resulted in aromatisation of the B ring and racemisation of the A ring N-dimethyl group at C6 (see Figure 1). These diastereomers could be separated by HPLC-MS and it was shown that the bone-derived fluorescent compounds had the same retention times and MS as the acid treated products from tetracycline. This study provided unequivocal evidence that the Nubians had access to a tetracycline producing Actinomycetes, which they presumably used for medical purposes (treatment and/or prophylactic). Tetracycline antibiotics were not used in modern medicine until their re-discovery in the 1950s. Since then, several semi-synthetic and synthetic tetracycline drugs have been approved and are used to treat a variety of infections.

Figure 1. Bone was treated with HF, which liberated anhydrotetracycline diastereomers that were analysed by LC-MS and an authentic standard. The bone picture used was sourced from “Ancient brew masters tapped drug secrets”, Emory University 2010 (available here).

Some thoughts: It is fascinating that tetracycline fermentation broths were used at least 1,500 years ago. We don’t know what happened, but I hope that some of these people weren’t some of the first to be infected with drug-resistant bacteria. Although some traditional fermentation knowledge has survived (e.g. alcohol production and Chinese red yeast rice), I wonder if other crude antibiotics were used by the Nubians or other peoples, but no traces were left (or have been discovered yet). It was hypothesised that tetracycline-containing broths were drunk. However, the tetracycline production levels must have been quite high to leave multiple fluorescent bone staining bands. Perhaps concentration steps could have used such as cloth filtration and/or evaporation. Actinomycetes can also grow on solid media and there is a possibility that a grain could have been used in an analogous way to red yeast rice.