MRSA Infection

Basilea want authorization of ceftobiprole for the treatment of pneumonia in Europe

Basilea to file application for marketing authorization of ceftobiprole for the treatment of pneumonia | Reuters.

Basilea Pharmaceutica Ltd. (SIX:BSLN) today announced that it will apply in the second half of 2012 for approval of its antibiotic ceftobiprole in Europe. In addition, reporting of topline data for the alitretinoin U.S. phase III study for chronic refractory hand eczema will occur in the first quarter of this year. Basilea thus has the potential for two regulatory submissions in 2012. Basilea has completed investigator site audits of two international double-blind randomized controlled phase III studies of ceftobiprole for the treatment of severe community-acquired and hospital-acquired pneumonia. The audits included 26 investigator sites, covering more than one third of patients of both trials. On the basis of these audits and following health authority feedback on potential filing strategies, Basilea has decided to apply in the second half of 2012 for the approval of ceftobiprole in Europe for pneumonia treated in the hospital setting.

Anti MRSA drugs stumbling at final hurdle

FT.com / Mergermarket - Basilea in due diligence with Astellas, Shire over ceftobiprole partnership.

Ceftobiprole is a broad-spectrum cephalosporin (b-lactam) antibiotic with activity against a wide range of Gram-positive bacteria, including the ‘superbug’ MRSA and penicillin-resistant Streptococcus pneumonia as well as many dangerous Gram-negative bacteria. In addition to complicated skin and skin structure infections (cSSSI) - the indication that was rejected by regulators - Basilea had also sought to develop ceftobiprole for the treatment of hospital acquired pneumonia (HAP), but this has been on hold since a Phase III trial showed that ceftobiprole was had lower cure rates than the comparator drug in the ventilator acquired pneumonia subset of patients. As previously reported, Astellas has its own anti-MRSA antibiotic (of a different class) that it also developed for both cSSSI and HAP with partner Theravance (NASDAQ:THRX) but it was only approved in cSSSI by the US authorities who to date have rejected its HAP application and asked for additional Phase III trials. Theravance is said to be appealing this decision, while an approval decision for both indications is still pending in Europe. One anti-infectives expert questioned why Astellas would want to take on ceftobiprole when it has already partnered on telavancin. A second anti-infectives expert agreed that the antibiotics are too similar for Astellas to want both, but said if telavancin does not receive approval in HAP, Astellas may decide that it is a better investment to start again from scratch with ceftobiprole in the HAP indication and try and get it approved as the first b-lactam antibiotic that can kill MRSA pathogens in pneumonia. This would be the “holy grail” in HAP, the expert said, explaining that the b-lactam class of antibiotics can kill MRSA faster than the gold standard therapy available, generic vancomycin.

Ceftobiprole guidelines

Pharmacodynamics of empirical antibiotic monotherapies for an intensive care unit (ICU) population based on Canadian surveillance data — J Antimicrob Chemother.

Conclusions This study provides important comparative data on empirical antibiotic monotherapies in an ICU setting including preliminary data on ceftobiprole. Ceftobiprole was most active overall, but similar to meropenem, piperacillin/tazobactam (lowest target only) and cefepime when MRSA was excluded. Prolonged infusions in particular and high doses were effective at improving antibiotic PD.

Ceftobiprole good against MRSA

Comparative activity of ceftobiprole against Gram-positive and Gram-negative isolates from Europe and the Middle East: the CLASS study — J Antimicrob Chemother.

Some 5041 Gram-positive and 4026 Gram-negative isolates were included. Against Gram-positive isolates overall, ceftobiprole had the lowest MIC50 (0.5 mg/L), compared with 1 mg/L for its comparators (vancomycin, teicoplanin and linezolid). Against methicillin-resistant Staphylococcus aureus, all four agents had a similar MIC90 (2 mg/L), but ceftobiprole had a 4-fold better MIC90 (0.5 mg/L) against methicillin-susceptible strains. Only 38 Gram-positive isolates were confirmed as ceftobiprole resistant. Among Gram-negative strains, 86.9%, 91.7% and 95.2% were susceptible to ceftobiprole, ceftazidime and cefepime, respectively.

J&J Must Pay Basilea $130 Million for Drug License Breach

J&J Must Pay Basilea $130 Million for Drug License Breach - ABC News.

Johnson & Johnson must pay former Swiss partner Basilea about $130 million for breaching a license agreement for a superbug antibiotic, a Dutch arbitration tribunal has ruled. The Swiss biotech group, which was developing ceftobiprole with the U.S. healthcare company, said on Monday the amount awarded included lost milestone payments as well as damages. Earlier this year, Johnson & Johnson ended a partnering deal with Basilea, returning the rights to ceftobiprole to Basilea after European and U.S. authorities decided not to back the drug, citing doubts about how reliable the results of the trial were.

Basilea mounts last-ditch effort to gain quick ok for MRSA drug ceftobiprole

Basilea mounts last-ditch effort to gain quick ceftobiprole OK - FierceBiotech.

The ceftobiprole saga isn't finished yet. Basilea Pharmaceutica said this morning that J&J subsidiary Janssen-Cilag International has asked European regulators to re-examine their rejection of a marketing application for the superbug antibiotic ceftobiprole, a troubled program that has endured despite bickering partners and a cloud now hovering over its clinical trial process.

J&J Terminates MRSA Drug (Ceftobiprole) Partnership

J&J Terminates MRSA Drug Partnership.

Johnson & Johnson terminated a partnership to develop a highly touted drug for MRSA and other dangerous skin infections after European regulators rejected it over concerns that testing data isn't reliable. Switzerland's Basilea Pharmaceutica Ltd. discovered the compound, called ceftobiprole. The company had been J&J's partner since granting the world's largest maker of health care products an exclusive worldwide license for it four years ago. But on Friday, Basel-based Basilea said the European Committee for Medicinal Products for Human Use refused to approve the drug, and Basilea regained full, global rights to it after J&J backed out of their deal. It said there would be a transition period to ensure proper management of ongoing testing, manufacturing and other activities "at no cost to Basilea."

Basilea says superbug drug gets positive opinion

UPDATE 1-Basilea says superbug drug gets positive opinion | Industries | Healthcare | Reuters.

ZURICH, Nov 21 (Reuters) - Basilea Pharmaceutica's (BSLN.S: Quote, Profile, Research, Stock Buzz) MRSA superbug antibiotic ceftobiprole has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of complicated skin and soft tissue infections, the Swiss biotech company said on Friday. The drug will be marketed under the Zevtera trade name in Europe. Recommendations for marketing approval by the CHMP are usually endorsed by the European Commission within a couple of months. Earlier this month ceftobiprole -- co-developed with Johnson & Johnson's (JNJ.N: Quote, Profile, Research, Stock Buzz) Janssen-Cilag unit -- received approval in Switzerland for the treatment of complicated skin and soft tissue infections including diabetic foot infections.

Ceftobiprole - another glowing report

Link: Comparative Study of the Susceptibilities of Major Epidemic Clones of Methicillin-Resistant Staphylococcus aureus to Oxacillin and to the New Broad-Spectrum Cephalosporin Ceftobiprole -- Chung et al. 52 (8): 2709 -- Antimicrobial Agents and Chemotherapy.

In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we examined the susceptibilities of the relatively few pandemic methicillin-resistant S. aureus (MRSA) clones that are responsible for the great majority of cases of staphylococcal disease worldwide. We also included in the tests the highly oxacillin-resistant subpopulations that are present with low frequencies in the cultures of these clones. Such subpopulations may represent a natural reservoir from which MRSA strains with decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR against MRSA strains with reduced susceptibility to vancomycin and against MRSA strains carrying the enterococcal vancomycin resistance gene complex. BPR was shown to be uniformly effective against all these resistant MRSA strains, and the mechanism of superb antimicrobial activity correlated with the strikingly increased affinity of the cephalosporin against penicillin-binding protein 2A, the protein product of the antibiotic resistance determinant mecA.

Ceftobiprole Kills MRSA

Link: Activities of Ceftobiprole, Linezolid, Vancomycin, and Daptomycin against Community-Associated and Hospital-Associated Methicillin-Resistant Staphylococcus aureus -- Leonard et al. 52 (8): 2974 -- Antimicrobial Agents and Chemotherapy.

We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC50 and MIC90 values were 1 and 2 µg/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested.

Ceftobiprole matches Vancomycin in combating MRSA

Link: HighWire Press -- Medline Abstract.

Ceftobiprole has so far demonstrated a good safety profile in preliminary studies with similar tolerability to comparators. The broad-spectrum activity of ceftobiprole may allow it to be used as monotherapy in situations where a combination of antibacterials might be required. Further clinical studies are needed to determine the efficacy and safety of ceftobiprole and to define its role in patient care.

Ceftobiprole is MRSA effective

Abstract.

Multidrug resistant strains of Staphylococcus aureus continue to increase in frequency worldwide - both in hospitals and in the community - raising serious problems for the chemotherapy of staphylococcal disease. Ceftobiprole (BAL9141) - renamed BPR - the active constituent of the prodrug ceftobiprole medocaril (BAL5788) is a new cephalosporin which was already shown to have powerful activity against a number of bacterial pathogens including S. aureus. In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we examined the susceptibility of the relatively few pandemic MRSA clones that are responsible for the great majority of staphylococcal disease worldwide. We also included in the tests the highly oxacillin resistant subpopulations that are present with low frequencies in the cultures of these clones. Such subpopulations may represent a natural reservoir from which MRSA strains with decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR against MRSA with reduced susceptibility to vancomycin and against MRSA carrying the enterococcal vancomycin resistant gene complex. BPR was shown to be uniformly effective against all these resistant MRSA strains and the mechanism of superb antimicrobial activity correlated with the strikingly increased affinity of the cephalosporin against penicillin binding protein 2A (PBP2A) - the protein product of the antibiotic resistance determinant mecA.

Ceftobiprole effective against MRSA

Link: In vitro activity profile of ceftobiprole, an anti-MRSA cephalosporin, against recent Gram-positive and Gram-negative isolates of European origin -- Pillar et al. 61 (3): 595 -- Journal of Antimicrobial Chemotherapy.

Ceftobiprole activity against MRSA (MIC90 2 mg/L) was 4-fold less than the activity against methicillin-susceptible S. aureus (MIC90 0.5 mg/L) and a similar trend was observed for methicillin-resistant CoNS (MIC90 2 mg/L) and methicillin-susceptible CoNS (MIC90 0.25 mg/L). Activity against S. pneumoniae (MIC90s: penicillin-susceptible, 0.015 mg/L; -intermediate, 0.25 mg/L; -resistant, 0.5 mg/L) was comparable to that of ceftriaxone. Ceftobiprole activity against Enterobacteriaceae (MIC90s: ceftazidime-susceptible, 0.12 mg/L; non-susceptible, >32 mg/L), P. aeruginosa (MIC90s: ceftazidime-susceptible, 8 mg/L, non-susceptible, >32 mg/L) and Acinetobacter spp. (MIC90: >32 mg/L for imipenem-susceptible and non-susceptible) was comparable to that of cefepime. As with cefepime, ceftobiprole activity was decreased among cephalosporin-resistant isolates of Gram-negative bacilli [extended-spectrum β-lactamase (ESBL) or non-ESBL mediated]. Conclusions: Ceftobiprole demonstrated potent in vitro activity against MRSA and showed activity against key Gram-negative bacilli comparable to that of cefepime. Given this broad spectrum of activity, ceftobiprole appears well suited for development and use in the treatment of a variety of healthcare-associated infections.

Positive Data On Ceftobiprole

Link: Johnson & Johnson Unit Reveals Positive Data On Ceftobiprole.

Johnson & Johnson's (JNJ) Pharmaceutical Research & Development unit said results from a Phase III trial showed that its investigational antibiotic ceftobiprole was found to clinically cure 86% of patients with diabetic foot infections, including some infections that were caused by methicillin-resistant Staphylococcus aureus (MRSA). The company said the trial, which enrolled 257 patients, showed ceftobiprole was well tolerated in the treatment of complicated skin and skin structure infections, including diabetic foot infections.

New drug works on CA MRSA

Link: PharmaLive:

With positive data reported for two pivotal trials in complicated skin and skin structure infections (cSSSI) ceftobiprole is approaching regulatory filing. Further evidence of the microbiological and pharmacokinetic profiles of this investigational compound was presented at ECCMID. Ceftobiprole has a broad in vitro spectrum, in particular activity against MRSA (Methicillin Resistant Staphylococcus aureus). In vitro susceptibility testing showed potent activity against all staphylococci collected in the first phase III cSSSI study, including MRSA and other multi-drug resistant pathogens (P2027). Testing these strains for the PVL gene, a marker for staphylococcal virulence, showed that the potential clinical efficacy of ceftobiprole is not impaired by the presence of this marker (P1321, O120). The antibacterial activity of ceftobiprole against Gram-positive organisms, including MRSA, is once more demonstrated in various in vitro studies (P710, P781, P784). Furthermore, ceftobiprole had the most potent activity of all beta-lactams tested against pneumococci that were not susceptible to ceftriaxone, selected from a recent U.S. collection of clinical isolates (P2025), supporting the potential use of ceftobiprole in the treatment of pneumonia.

Basileas MRSA drug performs well in late-stage trial

Link: Pharmaceutical Business Review

    Swiss biotech firm Basilea Pharmaceutica has received positive results for its first comparative phase III trial with ceftobiprole as a treatment for MRSA.  Ceftobiprole showed a high cure rate and was safe and well tolerated. This first-in-class anti-MRSA broad-spectrum cephalosporin is being developed in partnership with Cilag AG International, a Johnson & Johnson company.

ceftobiprole medocaril an alternative to vancomycin?

Link: Antimicrobial Agents and Chemotherapy.

After 7 days of therapy with ceftobiprole medocaril or vancomycin, average counts of MRGR3 decreased significantly (P < 0.02) by 0.68  0.28 (n = 29) and 0.88  0.22 (n = 28) log CFU/ml of tissue cage fluid, respectively, compared with cages of untreated animals, but were not significantly different from each other. No resistant mutants were detected on ceftobiprole-supplemented agar following therapy with this cephalosporin. The in vivo activity of ceftobiprole medocaril against chronic MRSA foreign-body infections was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations.

Ceftobiprole closer to approval

Link: Basilea

The growing incidence of serious infections caused by antibiotic-resistant bacteria is a matter of increasing global medical concern. Ceftobiprole (BAL5788) is the first of a new class of broad-spectrum cephalosporins with bactericidal activity against a number of gram-positive resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA) designed for treating patients with serious hospital infections. Ceftobiprole offers potent bactericidal activity against MRSA, penicillin-resistant Streptococcus pneumoniae (PRSP) and other major gram-positive bacterial pathogens as well as against gram-negative bacteria, similar to that of third-generation cephalosporins.

Basilea Antibiotic Ceftobiprole

Link: Basilea

BASEL, Switzerland, Feb. 3, 2005 (PRIMEZONE) -- Basilea Pharmaceutica AG announced today that it has entered into an exclusive worldwide agreement with Cilag AG International, a Johnson & Johnson company, to develop, manufacture and market ceftobiprole, Basilea's novel broad-spectrum cephalosporin antibiotic that has activity against methicillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole is in phase III clinical trials in complicated skin and skin structure infections and hospital-acquired pneumonia trials are in preparation. Both indications have been granted fast track designation by the U.S. Food & Drug Administration.

Potent new drug has 3rd test

Link: PrimeZone's News Room.

Ceftobiprole is the first of a new class of broad-spectrum cephalosporin antibiotics that was specially designed to bind the mutated targets in MRSA resulting in potent bactericidal activity towards MRSA and penicillin-resistant Streptococcus pneumoniae (PRSP). Ceftobiprole has not only maintained a broad-spectrum profile targeting other Gram-positive as well as Gram-negative pathogens, but has also shown a low potential to induce resistance in vitro.  In March 2003 the U.S. Food and Drug Administration granted BAL5788 Fast-Track designation for the treatment of complicated skin and skin structure infections due to methicillin-resistant Staphylococcus species, which has been followed by an additional designation in June 2004 for the treatment of hospital-acquired pneumonia including