Piperacillin/tazobactam: what will the future be like?

Piperacillin combined with the .-lactamase inhibitor tazobactam was approved for the first time by the FDA in 1993. The introduction of piperacillin/tazobactam into the market was associated with the following indications: 1) treatment of nosocomial pneumonia in combination regimens, 2) community-acquired pneumonia (moderate severity only caused by .-lactamase–producing H. influenzae), 3) appendicitis (complicated by rupture or abscess) or peritonitis, 4) uncomplicated and complicated skin and skin structure infections, and 5) postpartum endometritis or pelvic inflammatory disease cause by .-lactamase–producing E. coli. Today, piperacillin/tazobactam is considered as a golden standard in the empirical treatment of infections caused by P. aeruginosa, methicillin-resistantS. aureus, E. coli, and A. Baumanii. The latter is considered a major cause of healthcare-associated infections. Several studies reported piperacillin/tazobactam to possess a slight propensity to induce bacterial resistance. To further ensure the quality standard for injectable formulations, introduced by USP and EP in 2005, this formulation was modified by the Company through addition of citrate buffer and EDTA as excipients, to improve formulation robustness against pH drop in storage (leading to precipitation of insoluble piperacillin acid) and degradation of the dissolved drugs in presence of metal ions (particularly zinc thatenhances the beta-lactam ring opening of piperacillin andforms insoluble complexes with piperacillin). An excessive amountof particulate matter may cause adverse drug reactions (ADRs, including phlebitis, pulmonary granulomas and dysfunctions, local tissue infarction and death). The ADRs induced by injectable formulations may be more frequent and severe in critical patients and in infants and are difficult to be recognized, so to be improperly treated without discontinuation of the drug treatment, and thus represent a severe matter from both ethic and economic viewpoints. In 2007 the piperacillin/tazobactam patent expired and in 2009, the generic piperacillin/tazobactam formulations were marketed. No doubt that generic drugs allow a considerable saving. Recently, Jones et al. (2008) and Moet et al. (2009), by in vitro tests on E.coli, S.aureus and P.aeruginosa, have demonstrated several generic formulations that possess a reduced antibacterial efficacy compared to the branded product and a high variability in the effectiveness among lots of the same generic formulations, probably due to a reduced amount of active compound in formulations or at chemical-physical phenomena (eg, hydrolysis, polymerization). This could be because the generic formulations, unlike of branded formulations, do not contain citrate buffer and EDTA. The generic piperacillin/tazobactam formulations can allow the SSN to save considerable resources, to be differently allocated in the complex management of public health. To avoid risks for critical patient health (unsuccessful therapy, phlebitis, pulmonary granulomas, dysfunctions and death),additional consumption of economic resources (needed to treat possible ADRs, prolonged hospitalization), emerging resistant bacterial strains and consequent reduction of antibacterial effect, generic formulations must ensure the same high standard of quality and safety as well as the brand-name drug.