Post contributed by Glenn Whiteside, Product Specialist for AdisInsight

I have a mate, let’s call him Steve, actually his name is Steve, and several years ago he noticed that the big toe on his right foot was turning black. Diagnosis revealed that he had poor circulation to his lower leg and foot because of venous occlusion caused years ago when he was stomped on in a rugby game. The long and short of it was that his toe needed to be amputated and a stent put into a vessel in his leg to fix the problem. Unfortunately for Steve and the three other guys in his room, they were all infected with MRSA (methicillin resistant Staphlococcus aureus). Steve ended up having two further amputations on his leg to try to stop the spreading infection. He tried every antibiotic in the arsenal, but none of them stopped the relentless progress of the infection, instead the bacteria just kept on eating his tissues. Steve was lucky in a way because he lived to tell his tale, albeit without the lower half of his leg.

Resistance to antibiotics is one of the biggest threats to global health today. It can affect anyone, at any age, in any country. Bacterial resistance to drugs occurs naturally as bacterial populations evolve, but humans have accelerated it by misuse of antibiotics in both human and animal populations. Changes in modern medicine have also helped exacerbate the problem because they can lower a patient’s resistance to infection. Drug resistance is not a new phenomenon. It’s an ever evolving problem which comes about when drugs kill off susceptible organisms and leave resilient strains behind. These survivors then multiply, and over time become extremely resistant to frontline medicines. Up until quite recently, we have always had back-up antibiotics, when initial treatments fail, but nowadays these back-up drugs are also proving ineffective in knocking out the resistant strains. We don’t need to stretch the imagination too far to envisage a time when routine operations like hip and shoulder replacements, organ transplants, chemotherapies and surgeries like caesarean sections will become too dangerous to perform without effective antibiotics. What’s even more frightening is that the antibiotic drug development pipeline is not looking at all robust.

What we desperately need are new classes of antibiotics capable of killing these superbugs and slowing down the antibiotic-resistant evolution. Indeed, recently launched agents with innovative mechanisms capable of addressing multi-drug resistance have, unsurprisingly, been shown to receive favourable reimbursement/access decisions that can be leveraged during price negotiations. However, it is unlikely that successful treatment will involve the use of antibiotics alone. We will also need to develop medicines that are capable of priming the patient’s own immune system, which together with the antibiotics will eradicate the invaders.

So what’s in the pipeline?

AdisInsight lists a number of mid-to-late stage clinical development programmes targeting complicated infections and resistant bacteria. Some of these drugs have shown considerable promise, and providing there are no major hiccups in their development programmes they should soon be available for patient use.

Omadacycline is a first-in-class aminomethylcycline, in development with Paratek Pharmaceuticals, for the treatment of serious and antibiotic-resistant bacterial infections in both the hospital and community settings. The drug belongs to the tetracycline class and shows broad-spectrum activity against Gram-positive, Gram-negative, anaerobic and atypical bacteria. Omadacycline is the first lead compound selected from this class to progress to late stage clinical trials. Currently testing of intravenous and oral formulations of the drug is underway worldwide for the treatment of acute bacterial skin and skin structure infections (ABSSSI), and community-acquired bacterial pneumonia.

Shionogi has an injectable cephem cephalosporin antibiotic called cefiderocol that it’s developing for the treatment of Gram-negative bacterial infections. To date the drug has exhibited robust efficacy against a broad spectrum of Gram-negative bio-threat bacteria in vitro and Shionogi is poised to file a New Drug Application with the US FDA in 2017 followed by a marketing application in Europe in 2018. The drug exploits an iron-uptake mechanism and is actively transported into bacterial cells where it accumulates in the periplasmic space and binds receptors to inhibit cell wall synthesis. Shionogi believes that cefiderocol will have activity against a wide range of drug-resistant organisms, including those with diverse mechanisms of multidrug resistance.

Achaogen’s plazomicin is a next generation aminoglycoside that is in phase III development for the treatment of multidrug-resistant bacterial infections. Aminoglycosides kill bacteria by inhibiting protein synthesis and by disrupting the integrity of bacterial cell membranes. Plazomicin has shown good activity in terms of increased survival rates and in lowering rates of serious disease-related complications compared with Colostin. The US FDA has given the drug a development boost by granting breakthrough therapy status for bloodstream infections, as well as Qualified Infectious Disease Product (QIDP) designation for hospital-acquired bacterial pneumonia and other complicated bacterial infections. Achaogen plans to submit a New Drug Application to the US FDA in 2017 and a Marketing Authorisation Application to the EMA in 2018.

Tetraphase Pharmaceuticals is developing eravacycline, a late-stage, broad-spectrum small-molecule tetracycline (fluorocycline) antibiotic, for the treatment of multidrug-resistant Gram-negative infections, including carbapenem-resistant Escherichia coli and Klebsiella spp. The compound acts as a protein 30S ribosomal subunit inhibitor. It has initially been investigated in patients with complicated intra-abdominal infections, but other target indications include complicated urinary tract infections, hospital-acquired pneumonia and complicated skin and soft tissue infections. Eravacycline is under review in the EU, for the treatment of complicated intra-abdominal infections. Clinical development is underway for intra-abdominal infections, respiratory tract infections and urinary tract infections.

Exoxemis is developing E 101, a porcine myeloperoxidase-based therapy for the treatment of bacterial and viral infections. The therapy has been formulated as a solution for local delivery, and has demonstrated potent and versatile antimicrobial activity, even in resistant strains. E 101 selectively binds to target microbes then generates reactive singlet oxygen free radicals which trigger oxidative stress and death of microbes with minimal toxicity to host tissue. If approved, Exoxemis had said it believed E 101 could be the first antiseptic agent available for direct administration to surgical wounds. However, no recent reports of on-going development have been published for this agent, although the company is keen to seek opportunities for licensing its technology and products such as E 101 in a bid to get new drugs to market.

Other drugs showing potential include solithromycin, a fourth generation macrolide, from Cempra Pharmaceuticals is preregistration for oral and IV formulations in the USA for community-acquired pneumonia, and late phase for a range of other indications globally; and CF-301 from ContraFect, a recombinant bacteriophage-derived lysin in Phase II development for the treatment of Staphylococcal aureus infections, including bacteraemia and endocarditis, also with fast-track status.

If we want drug makers to take up the antibiotic challenge then there needs to be some incentives for them to do so. The return on investment coupled with diminishing prospects of getting an effective antibiotic drug to market over the past 2 decades means that pharma companies have preferred to invest in other areas where they’ve seen better prospects. There is a whole gambit of approaches to take here including investigations into immunotherapy, drug combination therapy, drug administration routes, and revisiting past failures. However, without the right balance of regulatory and financial incentives, market positioning and regulatory restrictions on generic drug entry we are not going to truly incentivise developers which means that we won’t be getting an effective arsenal to physicians and patients any time soon.

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