Many successful products combine ß-lactam antibiotics and ß-lactamase inhibitors: Augmentin® (amoxicillin plus clavulanic acid, GSK); Unasyn® (ampicillin plus sulbactam, Pfizer), and Tazocin® (piperacillin plus tazobactam, Wyeth).  These products achieved combined sales of $1.2 billion in 2003. 

There is an enormous unmet need in this area, particularly for compounds which introduce a second mode of anti-microbial action to reduce the incidence of bacterial resistance.

Sales for the top-earning antibiotics in the hospital sector in 2005

Notes

1 Ceftriaxone has been investigated as a potential cephalosporin partner for  AM-112.  The combination has particular impact on Enterobacter species. 2 Amura BLIs enhance the efficacy of piperacillin against isolates of E. coli, P. vulgaris, C. freundii, S. marcescens and Morganella species. 3 The combination of imipenem and AM-112 is synergistic against MRSA. 4 The combination of meropenem and AM-112 is superior to the use of meropenem alone.  * Elan’s Maxipime® and Roche’s Rocephin® are cephalosporins, a perennially successful class of ß-lactam antibiotics.  The market for cephalosporins was $4.25 billion in 2003.  Despite patent expiries in intervening years the market is still expected to be worth $2.5 billion in 2008, since many cephalosporin products still maintain sales of between $200 million and $400 million p.a. including: cefcapene pivoxil (Shionogi), cefdivinir (Abbott/Astellas/Xian Janssen) and cefuroxime axetil (GSK).  Notably, the cefcapene pivoxil sales arise solely in the Japanese market, which accommodates over twenty different cephalosporin products, many of which generate over $150 million p.a.  Japan is also seeing a dramatic increase in the incidence of resistance to these drugs.

III. Amura ß-lactamase Inhibitors

AM-112, AM-119 and AM-122 represent a distinct class of ß-lactamase inhibitor.  These show synergistic effects when partnered with ß-lactam drugs such as cephalosporins, penicillins and carbapenems.

Whilst effective against Class A ß-lactamases, Augmentin®, Unasyn® and Tazocin® have not been as successful against Class C, D or extended spectrum ß-lactamases (ESBLs).  AM-112. AM-119 and AM-122 overcome or markedly diminish the resistance of many pathological bacteria through their strong activity against Class C ß-lactamases, but retain significant activity against Class A, Class D and ESBLs making them potent broad spectrum combination candidates for first-line therapy in nosocomial infections.

1. Cephalosporins

Ceftazidime, cefoperazone and cefepime show bactericidal activity against Pseudomonas aeruginosa and Acinetobacter baumanii when protected by AM-112.  AM-119 and AM-122 also show an impact on these pathogens in combination with ceftazidime.  In addition, AM-119 is particularly effective against Enterococci as demonstrated by the successful challenge of twenty-four hospital isolates of ceftazidime-resistant strains: in all cases except one, the presence of AM-119 was sufficient to overcome the resistance to ceftazidime. 

Comparisons of the fold reduction in MICs for AM-112 and its analogue AM-122 in combination with ceftazidime (CAZ) compared to ceftazidime (CAZ) alone

2. Penicillins

The combination of ceftazidime and AM-112 is generally more effective than that of piperacillin and AM-112 against many pathogens.  However, there are exceptions in which the combination of piperacillin and AM-112 is the more potent.  In the case of P. vulgaris V3-DEF neither ceftazidime alone nor the ceftazidime/AM-112 combination has any impact on this strain.  In contrast, piperacillin on its own does, and its efficacy is improved sixteen-fold in the presence of AM-112.

3. Carbapenems

AM-112 shows a mixture of outcomes in the presence of imipenem and meropenem ranging from additive improvements in bacteriocidal performance to synergistic effects in a number of cases.  Notably, the combination of imipenem and AM-112 is the first Amura BLI combination to show efficacy against MRSA.  Remarkably, AM-112 has no bacteriocidal activity against MRSA on its own.

4. Non ß-lactam drugs

AM-112 also has an unexpected synergy with non-ß-lactam drugs, for example, showing efficacy when used against vancomycin-resistant Enterococci (VREs). This mode of action is distinct from the compound’s ß-lactamase activity because VREs do not express ß-lactamases (see PCT/GB02/01162).

IV. In vivo models of bacterial infection

Several rodent models of bacterial infection demonstrate the in vivo effect of Amura ß-lactamases in concert with ceftazidime.  In all cases, the presence of the Amura ß-lactamase enhanced the susceptibility of the infectious bacteria to ceftazidime and reduced significantly the amounts of ceftazidime required in the effective dose (reductions ranging from >fifty-fold to two-fold).

1. Staphylococcus aureus 3816

In a mouse model of Staphylococcus aureus (expressing Class C ß-lactamases) infection, AM-112 was used at concentrations as low as 1 mg/kg in combination with ceftazidime. AM-112 showed strong activity with ED50 values of 1.2 mg/kg and 1.0 mg/kg in ratios of 4:1 and 1:1, respectively, with ceftazidime.  (In the same experiment oral dosing of AM-112 alone required ten-fold higher levels of AM-112 to achieve comparable ED50 values as those obtained via the subcutaneous route for the drug used in isolation, demonstrating that the latter route better suits the pharmacokinetics of this compound.)

2. Enterococcus cloacae P99

In a further study employing a mouse model of infection with Enterococcus cloacae P99 expressing Class C ß-lactamases, the efficacy of AM-112 in combination with ceftazidime was confirmed.  Moreover, when clavulanic acid was presented as the partner ß-lactamase inhibitor against the same infection, the lowest ED50 values were 44 mg/kg and 25 mg/kg when it was used in ratios of 1:1 and 4:1 with ceftazidime.  In contrast, AM-112 had ED50 values of 2 mg/kg and 3 mg/kg when used in ratios of 1:1 and 4:1, respectively.

3. Escherichia coli SHV-5

Escherichia coli SHV-5 which expresses extended spectrum Class C ß-lactamases proved susceptible to the combination of AM-112 with ceftazidime.  At ratios of 1:1 and 2:1 (ceftazidime: AM-112) the ß-lactamase inhibitor had ED50 values of 2 mg/kg and 1 mg/kg, respectively. 

The combined pharmacologic effect, the low dosages, the non-oral route of delivery and the potential to include an off-patent partner compound together promise a cost-effective and clinically effective combination i.v. product.

V. Intellectual Property

The commercial value of this compound series is consolidated by a long patent life.  Amura’s patent estate numbers approximately a hundred patents comprising: fifty-two issued or granted patents (including two US patents, three European patents and a Japanese patent) and a further forty seven pending patent applications (including: three US patents, two European patents and two Japanese patents). 

Amura’s ß-lactamase patent estate

VI. Contact Details

To receive a non-confidential Information Summary, or to discuss your in-licensing needs, please contact:

Dr. Manoj Ramjee
Tel: +44(0)1223 839797
Email: amura@amura.co.uk