There is a clear and urgent need for novel antibacterial agents – particularly those targeting multidrug-resistant Gram-negative and other bacterial strains, but resistance to currently available agents continues to increase due to widespread misuse of drugs and poor patient compliance, causing considerable morbidity and mortality.
Concern has mounted over the last decade, leading to the recent launch of regulatory initiatives in the European Union (EU) and the US aimed at stimulating antibacterial drug development.
Such drugs use mechanisms such as targeting the plasma membrane or cell wall synthesis to disrupt or prevent bacterial cell growth and division. Antibacterial agents that interfere with cell wall synthesis include some of the most frequently used antibacterial agents in existence and many are bactericidal, making them highly appealing.
Two major classes – beta-lactams (eg penicillins, ciclosporins, monobactams and carbapenems) and the glycopeptide antibiotics (eg vancomycin) – control Gram-negative and Gram-positive bacterial infection via inhibition of cell wall synthesis and have been used effectively for many decades. The beta-lactams are generally broad-spectrum antibacterials that inhibit a wide range of pathogenic bacteria, but are susceptible to drug-inactivating beta-lactamases produced by some bacterial strains. Glycopeptides have high activity against staphylococci, but their effectiveness against many types of enterococci has been reduced by resistance. Both function by disrupting the synthesis of peptidoglycan – a major component of the cell wall vital for structural integrity. As a result, the growing bacteria are unable to synthesise new cell wall, leaving them extremely vulnerable to cell lysis.
New molecular entities
The number of antibacterial new molecular entities (NMEs) that have reached the marketplace has dramatically diminished over the past few decades, and no new class of antibacterials to treat Gram-negative pathogens has been developed since the early 1960s.
Despite this, there have been two new antibacterial NMEs that have been recently marketed and that target the bacterial cell wall: ceftaroline fosamil (Teflaro, Zinforo; Forest Laboratories, AstraZeneca), a fifth-generation, intravenously administered cephalosporin; and telavancin (Vibativ; Theravance), a once-daily, intravenously administered bactericidal lipoglycopeptide.
Ceftaroline fosamil inhibits penicillin-binding proteins involved in bacterial cell wall synthesis, thus causing reduced bacterial cell replication and cell death. It was launched in the US in 2011 to treat community-acquired bacterial pneumonia (CAP) and acute bacterial skin and skin structure [or soft tissue] infections (SSSIs) and methicillin-resistant Staphylococcus aureus (MRSA). In the EU, the product is registered for treatment of CAP and complicated SSSIs, and has been launched in countries such as the UK, the Netherlands, Australia and Malaysia, and a regulatory application is expected to be filed in China in the first half of 2014.
The antibacterial effects of telavancin are mediated by multiple mechanisms, including inhibition of peptidoglycan synthesis and increased bacterial cell membrane permeability – this dual mechanism is thought to be responsible for the low frequency of spontaneous resistance reported. It was first launched in 2009 in the US for complicated SSSIs caused by Gram-positive bacteria and then approved in June 2013 to treat nosocomial and hospotal/ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of S. aureus (methicillin-resistant and MRSA). In September 2011, the European Commission approved telavancin for the treatment of adults with HABP/VABP, known or suspected to be caused by MRSA; however, this marketing authorisation was suspended in May 2012 due to concerns regarding renal toxicity.
Inhaled aztreonam
Several agents, such as inhaled aztreonam (Cayston; Gilead Sciences) have been on the market for some years, but are undergoing investigation in new indications. Inhaled aztreonam is a monobactam currently marketed for treatment of adults with a range of infections caused by Gram-negative bacteria (including cystic fibrosis-associated respiratory tract infections [CF-RTIs] and CF-associated pulmonary Pseudomonas aeruginosa infection), and is in pre-registration (EU) and phase III development (US) for these indications in children. In June 2012, the European advisors recommended its approval for use in children aged 6 years with CF and chronic P. aeruginosa pulmonary infections. Inhaled aztreonam is also in phase III development for bronchiectasis, Burkholderia and other Gram-negative bacterial infections.
Gram-negative infections
An intravenous (IV), fixed-dose combination (FDC) of the beta-lactamase inhibitor avibactam plus broad-spectrum cephalosporin – ceftazidime (AstraZeneca) – is in phase III trials for nosocomial Gram-negative infections, particularly due to drug-resistant strains. Indications include complicated urinary tract and intra-abdominal infections caused by Gram-negative pathogens, and nosocomial pneumonia in hospitalised patients.
The IV FDC ceftolozane plus beta-lactamase inhibitor tazobactam (Cubist Pharmaceuticals) is in phase III development for first-line treatment of nosocomial Gram-negative infections, caused by multidrug-resistant Pseudomonas aeruginosa and Enterobacteriaceae (eg Escherichia coli, Klebsiella pneumoniae) and VABP, and complicated intra-abdominal (cIAI) and urinary tract infections (cUTIs). For the last two indications, US regulatory filings are expected by the end of 2013, followed by EMA submission. Ceftolozane/tazobactam has received FDA Qualified Infectious Disease Product (QIDP) designation and fast-track status for HABP/VABP, cUTI and cIAI. The first phase III trial in VABP (VECTOR), which began recruitment in July 2013, will compare the efficacy and tolerability of IV ceftolozane/tazobactam with piperacillin/tazobactam in 300 patients.
An FDC of meropenem (Aqua Vitoe Laboratories), a broad-spectrum carbapenem, and tazobactam, a beta-lactamase inhibitor, is in phase III development for the treatment of Gram-negative bacterial infections.
Typhoid
An oral FDC of the third-generation cephalosporin cefixime and fluoroquinolone ofloxacin (Akums Drugs & Pharmaceuticals) has completed a phase III trial in India for treatment of typhoid. The same company is also developing the oral FDC cefpodoxime/ofloxacin for the treatment of patients with respiratory tract infections and typhoid, which is also in phase III development in India.
Gram-positive infections
An IV formulation of oritavancin (The Medicines Company), a semisynthetic lipoglycopeptide and cell wall synthesis inhibitor, is in phase III development for the treatment of acute bacterial cSSSIs caused by Gram-positive bacteria, including MRSA and vancomycin-resistant staphylococcal strains. In November 2013, the US FDA granted oritavancin QIDP designation, confering upon it review and exclusivity benefits in acute bacterial cSSSIs.
Dalbavancin (Pfizer/Vicuron Pharmaceuticals) is a second-generation, semi-synthetic, IV lipoglycopeptide antibiotic that inhibits bacterial cell wall biosynthesis by binding to the C-terminal d-alanyl-d-alanine of growing peptidoglycan chains. In November 2013, it won priority review from the US FDA for acute bacterial SSSIs caused by susceptible Gram-positive bacteria (including MRSA). Dalbavancin has an improved dosing regimen and increased potency versus vancomycin against Gram-positive bacteria including MRSA and S. epidermidis (MRSE).
HT 61 (Helperby Therapeutics) is a small molecule, quinolone-derived compound, in phase III development in the UK for the treatment of Staphylococcal infections, both methicillin-sensitive and -resistant, as well as for Panton-Valentine leukocidin-producing S. aureus, and methicillin/mupirocin-resistant S. aureus infections. HT 61 is referred to as a fast-acting ‘antibiotic resistance breaker’ (ARB), which when combined with an old obsolete antibacterial agent, can rejuvenate it and make it active against highly resistant bacteria.
Tuberculosis
Two oral-based cell wall inhibitors are being investigated for the treatment of tuberculosis (TB). The nitro-dihydroimidazo-oxazole derivative Delamanid (Deltyba; Otsuka Pharmaceutical) inhibits mycolic acid synthesis and thus the formation of the mycobacterial cell envelope. Regulatory applications have been filed in the EU and Japan. However, the CHMP recommended against approval of the drug for treatment of pulmonary, multidrug-resistant tuberculosis (MDR-TB) in July 2013, when given in combination with an optimised background regimen. However, the CHMP subsequently reversed its negative opinion in November 2013 after Otsuka provided the EMA with data to support the drug’s effectiveness at six months. A decision is expected by the European Commission in early 2014.
Meanwhile, ethylenediamine antibacterial SQ 109 (Sequella, Infectex), which interferes with the incorporation of mycolic acid into the cell wall core, is in phase II/III (Russia) or phase II development (South Africa, Tanzania) for TB. Orphan drug status has been granted in both the US and the EU for this indication; fast-track status has also been granted in the US.
Time for a global commitment
The discovery of antibacterial drugs in the 1930s and 1940s was a transformative moment in human history – however, a global commitment to develop new drugs is needed. Increasing resistance remains a concern, but cell wall synthesis inhibitors have been shown to be highly effective. The small number of cell wall inhibitors in late-stage clinical development is very low – reflecting activity levels in the antibacterial field as a whole. It is hoped that the new regulatory initiatives in the EU and US will achieve the desired effect of stimulating advances in antibacterial development and accelerating the drug pipeline.