Title: Introduction: An international review of amdinocillin: A new beta-lactam antibiotic
Abstract: I n an era when the development of new antimicrobial agents is occurring at almost breakneck speed, it is not surprising that it is often difficult to distinguish one agent from another. Indeed, in many instances, it appears that newly developed antimicrobials are nothing more than variants on an already well established theme. This is particularly true for the new beta-lactam agents, including the second and third generation cephalosporins and the expanded spectrum penicillins. In such an environment, one could reasonably ask why additional agents should be developed, especially since it would appear that some of the current beta-lactam antibiotics approach perfection. A careful observer of the antibiotic scene, however, will be quick to point out that perfection has not yet been achieved. None of the presently available beta-lactam antimicrobial agents is totally free from adverse effects, and none is immune to the problems of antimicrobial resistance-either intrinsic or acquired. Thus the search for new and better agents goes on. Amdinocillin (formerly known as mecillinam) is a betalactam antibiotic that possesses unique properties that will be delineated in this symposium issue. Unlike most other beta-lactam antibiotics that utilize a number of different penicillin-binding proteins as their targets in the bacterial cell, amdinocillin binds specifically to a single penicillin-binding protein in gram-negative bacilli. This means that it possesses the potential for interacting with other beta-la&m antibiotics that have greater affinity for other binding sites. This unique property, which is at once an advantage and a drawback, sets amdinocillin apart from most of the other beta-lactam antibiotics currently under development. In this symposium issue, a series of investigators present studies that delineate the in vitro activity, pharmacokinetics, and clinicat efficacy of amdinocillin in a number of settings. Based on these papers one can obtain an accurate profile of the potential utility of this new and unique antibiotic. The first paper by Robert C. Moellering, Jr. is a summary of the rationale for the use of antimicrobial combinations and sets the stage for a number of in vitro and in vivo studies of amdinocillin in combination with other antimicrobial agents. This report points out that there are a number of mechanisms by which antimicrobial interaction may occur. Under favorable circumstances, this interaction results in enhanced antibacterial activity (synergism). However, there is also a potential for diminished activity by the combination (antagonism). Since this has been noted when combinations of two different beta-la&m antibiotics have been employed, it must be considered carefully when examining the utility of amdinocillin in combination with other beta-lactams. An article by Harold Neu follows and outlines current knowledge concerning the mechanism of action of betalactam antibiotics and provides the biochemical background for the subsequent articles, which deal with the in vitro and in vivo activity of amdinocillin alone and in combination with other agents. Dr. Neu points out that amdinocillin not only has unique properties as far as its affinity for penicillin-binding proteins is concerned, but that it is also relatively resistant to beta-lactamases. This latter property is also potentially important in the clinical efficacy of this new agent. The in vitro spectrum of activity of amdinocillin in combination with other agents is defined clearly in the paper by Roy Cleeland and Edwina Squires. As expected, amdinocillin showed marked enhancement of the spectrum of activity of a large number of beta-lactam agents tested in combination with it, with the single exception of moxalactam. Perhaps of even greater importance was the fact that antagonism was not a frequent occurrence when amdinocillin was combined with any of a number of beta-lactam antibiotics. It has been known for many years that the in vitro activity of beta-lactam antibiotics can be correlated with their ability to produce morphologic alterations in susceptible bacteria. Utilizing this principle, Michael Kramer and co-workers have carried out an extensive study of the morphologic effects of amdinocillin when combined with several beta-lactam antibiotics in vitro utilizing scanning electron microscopy. They were able to demonstrate morphologic effects due to the combination of amdinocillin with other beta-lactam antibiotics that were unique and were not seen when the beta-lactam antibiotics were utilized alone. Thus it appears that these authors have demonstrated the morphologic basis for antimicrobial synergism when amdinocillin is combined with other agents. It is relatively easy to define the in vitro activity of antibiotics alone and in combination, but it is often difficult to extrapolate from such studies to the clinical situation. Various models that more closely approximate conditions found in vivo have been employed in an attempt to bridge the gap between in vitro and in vivo studies. The article by John Anderson and Feri Eftekhar represents an example of the successful application of such a model. These authors utilized a model that reproduces many features of the milieu of the human urinary bladder to study the activity of ampicillin and amdinocillin combinations against urinary isolates of bacteria. Their results strongly suggest that such models may be more useful than in vitro studies alone in predicting the clinical utility of antibiotic combinations. Animal models have been widely utilized to demonstrate in vivo activity of antimicrobial agents alone and in combinations. Fred Gordin and Merle Sande summarize the current state of the art vis a vis the utilization of such models to study antimicrobial combinations. In their rabbit meningitis model they demonstrate that the synergistic interaction of amdinocillin and ampicillin results in much more effective therapy of Escherichia coli and Klebsiella pneumoniae meningitis and suggests a rational basis for the clinical trial of amdinocillin-beta-lactam combinations. No matter how effective a drug is in vitro or in vivo, if it does not possess attractive pharmacokinetic properties in man its clinical application may be very disappointing. Thus,