HELSINKI, June 8 /PRNewswire/ -- Ipsat Therapies announced today that oral P1A beta-lactamase met all end-points and provided protection for the normal gastrointestinal microflora in a phase 1 study in healthy subjects receiving intravenous piperacillin/tazobactam for 5 days.
P1A is the most advanced of Ipsat's portfolio of beta-lactamases. It is administered orally and designed to inactivate the residual amounts of certain beta-lactam antibiotics excreted into the patients' gastrointestinal tract, after intravenous administration of these antibiotics for serious infections, and to reduce the transmission of resistant bacteria.
The Phase I study,
IT-008, was a randomized, placebo-controlled, double-blind study in 52 healthy subjects. Sixteen subjects received P1A at doses of either 28mg or 56mg, or placebo, and 36 subjects received the same doses of P1A or placebo together with intravenous piperacillin/tazobactam four times daily for 5 days. P1A efficacy was evaluated by the quantity of piperacillin found in the faeces and the changes in faecal microflora as measured by the Similarity Index (SI). Gastrointestinal side effects and the overall tolerability of P1A alone and in combination with piperacillin/tazobactam were also evaluated.
At a dose of 28mg, P1A reduced piperacillin levels in the faeces to less than 5% compared to placebo and piperacillin was undetectable in the faeces at the 56mg dose. No P1A was detected in plasma and the plasma pharmacokinetics of piperacillin were unaffected by P1A at either dose, suggesting that P1A will not reduce the effectiveness of piperacillin/tazobactam as an anti-infective.
The faecal microflora was essentially unchanged when P1A at either dose was co-administered with piperacillin/tazobactam. The change in SI on day 8 was 38.9% (p0.001) more for placebo plus piperacillin/tazobactam than for P1A plus piperacillin/tazobactam.
P1A was well-tolerated. Diarrhoea was not reported in any of the 12 subjects receiving P1A 56 mg concomitantly with piperacillin/tazobactam, compared to 3 of 12 subjects receiving P1A 28mg and 6 of 12 subjects receiving placebo (p0.05).
We are excited by the outcome of this trial. It clearly shows the efficacy of Ipsat P1A in destroying harmful antibiotic in the gut and preserving the intestinal microflora, commented Rabbe Slatis, CEO of Ipsat Therapies.
Healthcare-associated infections are a major cause of death in developed countries. It is estimated that 7.5 million patients suffer from hospital infections each year and nearly 340,000 of them die. The financial costs associated with hospital infections are equally staggering - hospital-acquired infections result in up to $27.5 billion in additional health care expenses annually in the USA.
Prof. Yehuda Carmeli, of Tel Aviv University commented: In a recent study in our centre, new microbiologically-documented infection occurred after start of piperacillin/tazobactam in 20% of patients overall, and in 30% of ICU patients. Many of these infections were caused by micro-organisms which commonly colonise the gut prior to causing clinical disease. The changes to the normal gut microflora caused by broad-spectrum antibiotics like piperacillin make patients more vulnerable to colonisation by potential pathogens and subsequent serious infections. The role that P1A plays in protecting the normal gut flora may help to prevent such infections.
The spread of resistance to antibiotics is one of the most important issues we face in medicine today, said Carl-Erik Nord, Emeritus Professor of Microbiology at the Karolinska Institute, Stockholm. Appropriate use of antibiotics is one way of impacting this, but a therapy that helps to maintain colonisation-resistance, by protecting the normal gut microflora from the unwanted effects of antibiotics in the gastro-intestinal tract, could also be very beneficial.
Gut microflora and the Similarity Index
The human gastrointestinal tract harbors a diverse community of microorganisms consisting mainly of anaerobic bacteria. Denaturing gradient gel electrophoresis (DGGE) provides information about the intestinal bacterial microflora, including species that are difficult if not impossible to culture. DGGE separates ribosomal-RNA gene sequences of similar size, producing a molecular fingerprint profile of the microflora. These fingerprint profiles are compared to each other by computer analysis resulting in calculation of a Similarity Index (%) between the individual profiles.
The effect of antibiotic therapy on the composition of intestinal microflora is evaluated by comparing the DGGE fingerprint profile from a faecal sample before antibiotic treatment with the sample taken during / after treatment.
See P1A Recombinant B-Lactamase Prevents Emergence of Antimicrobial Resistance in Gut Microflora of Healthy Subjects during Intravenous Administration of Ampicillin, Antimicrobial Agents and Chemotherapy 2009; 53: 2455-2462
Notes to editors:
Ipsat Therapies Ltd is a private company focusing on the development of products in the anti-infective field. Ipsat's focus is primarily on the development of products for the prevention of antibiotic resistance, antibiotic-associated diarrhea and hospital associated infections. For more information please visit http://www.ipsat-ther.com. ---------------------------------
For further details please contact: Rabbe Slatis, CEO, Ipsat Therapies Ltd, Viikinkaari 4, FIN-00790 Helsinki, Finland, Tel: +358-40-840-6749 (mobile), Tel: +358-9-319-36-500 (office)