Advances in outpatient antimicrobial therapy: Loracarbef

Abstract

O ur understanding of the structure-activity relationships of antibiotics has increased dramatically since penicillin became available almost 50 years ago. This knowledge has enabled investigators to develop new agents with a variety of improvements compared with early antibiotics, including a wider spectrum of antibacterial activity, greater chemical stability, greater oral absorption with less effect on gastrointestinal flora, fewer side effects, more convenient dosing schedules, and fewer drug interactions. The progressive development of the fl-lactam antibiotics has included side chain modifications in their chemical structures, such as those that resulted in penicillinase-resistant penicillins, and nuclear ring alterations that have led to new classes of antibiotics, such as the cephalosporins. A recent addition to the/3-1actam antibiotics is the oral agent loracarbef, which represents a new carbacephem class. The carbacephems are similar in structure to the cephalosporins except that a methylene group in the tetrahydropyridine ring of the carbacephem nucleus has replaced the sulfur atom in the dihydrothiazine ring of the cephalosporin nucleus. This change renders the carbacephem nucleus more chemically stable than the corresponding cephalosporin nucleus. On June 13-15, 1991, an investigators' meeting was held in San Francisco, California, to discuss the preclinical and clinical data on loracarbef. The safety and efficacy results of clinical trials that compared loracarbef with oral antibiotics currently in use for a variety of bacterial infections--including acute bronchitis, acute exacerbations of chronic bronchitis, pneumonia, sinusitis, pharyngitis and tonsillitis, skin infections, pyelonephritis, and urinary tract infections--were reported at the meeting. Also included in the program was a clinical forum on pathogenesis of and therapy for common lung disorders. The focus of the clinical forum was the underlying mechanisms of respiratory dysfunction, including inflammation and airway reactivity in asthma, fibrosis in acute lung injury, and the effects of neutrophils on the lung, as well as new treatments in cystic fibrosis, such as aerosolization of therapeutic agents and somatic gene therapy. The articles in this supplement are based on the presentations and discussions at this meeting. Preclinical data on loracarbef indicate that this compound has broad in vitro activity against common pathogens (including fl-lactamase-producing organisms) and that it is well absorbed and clinically stable. In singleor double-blind, randomized clinical trials involving more than 9,000 patients, it was compared with other antibiotics for its ability to resolve a number of bacterial infections, including acute bronchitis, acute exacerbations of chronic bronchitis, pneumonia, sinusitis, pharyngitis and tonsillitis, otitis media, skin infections, urinary tract infections, and pyelonephritis. A data base of this size, which is unprecedented in comparative antibiotic trials, allows more reliable conclusions to be drawn concerning the safety and activity of the drugs studied. It also allows the analysis of special subpopulations, such as elderly and pediatric patients, both of whom frequently experience adverse effects from antibiotics. The results of these clinical trials indicate that the efficacy of loracarbef is comparable to that of the comparison agents and that it has a favorable safety profile, even in pediatric and geriatric patients. Most adverse events that occurred in the loracarbef-treated patients were mild and transient; diarrhea was the most common adverse reaction, but it was reported less frequently in the loracarbef patients than in those who received the comparison agents. The safety, efficacy, broadspectrum activity, and stability of loracarbef suggest that it is reasonable to consider this compound as an option when empirical therapy is indicated for a variety of common bacterial infections. The extensive clinical information provided in this supplement should enable the practicing physician to utilize loracarbef effectively in appropriate patients.