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The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies-variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues.

Widespread, increasing antibiotic resistance amongst the major respiratory pathogens has compromised traditional therapy of the major infective respiratory syndromes, including bacterial pneumonia and acute exacerbations of chronic bronchitis. Guidelines for antibiotic prescribing dating from the 1980s to 1990s, which attempted to address such problems, were commonly too prescriptive and difficult to apply, and took little account of end-user practice or locally prevalent resistance levels. Further confusion was caused by conflicting recommendations emanating from differing specialty groups. The evidence that such guidelines benefited either clinical outcomes or treatment costs has been disputed. They have probably had little effect on resistance emergence. We report the recommendations of an independent, multi-national, inter-disciplinary group, which met to identify principles underlying prescribing and guideline formulation in an age of increasing bacterial resistance. Unnecessary prescribing was recognized as the major factor in influencing resistance and costs. Antibiotic therapy must be limited to syndromes in which bacterial infection is the predominant cause and should attempt maximal reduction in bacterial load, with the ultimate aim of bacterial eradication. It should be appropriate in type and context of local resistance prevalence, and optimal in dosage for the pathogen(s) involved. Prescribing should be based on pharmacodynamic principles that predict efficacy, bacterial eradication and prevention of resistance emergence. Pharmacoeconomic analyses confirm that bacteriologically more effective antibiotics can reduce overall management costs, particularly with respect to consequential morbidity and hospital admission. Application of these principles should positively benefit therapeutic outcomes, resistance avoidance and management costs and will more accurately guide antibiotic choices by both individuals and formulary/guideline committees.

Background and Purpose-Several studies have implied an association between Chlamydia pneumoniae and atherosclerosis. Our research was designed to investigate the association of this organism with strokes and transient cerebral ischemia. Methods-Antibodies to C pneumoniae were measured in 176 patients with stroke or transient cerebral ischemia and 1518 control subjects with noncardiovascular, nonpulmonary disorders. Acute infection or reinfection was defined by IgG Ն512 or IgM Ն8 or fourfold rise in IgG, and previous infection was defined by IgG 64 to 256 or lgA Ն8. Logistic regression was used to examine the influences of ethnic origin, age, sex, smoking habit, diabetes mellitus, steroid medication, and social deprivation on antibody levels. Some patients underwent CT and carotid ultrasound examinations and cholesterol, triglyceride, fibrinogen, and von Willebrand factor estimations. Results-We found that 13.6% of stroke/transient ischemic attack (TIA) patients and 5.7% of control subjects had antibody titers suggesting acute C pneumoniae (re)infection, while 32.4% of stroke/TIA patients and 12.7% of control subjects had titers suggesting previous infection (PϽ.05). Stroke/TIA patients differed from control subjects in their levels of acute and previous infection, with adjusted odds ratios of 4.2 (95% CI, 2.5 to 7.1) and 4.4 (95% CI, 3.0 to 6.5), respectively. These did not differ notably between strokes resulting from major nonhemorrhagic infarcts, small-vessel infarcts, or hemorrhage. Cholesterol, triglyceride, fibrinogen, and von Willebrand factor concentrations showed no apparent association with titers. Conclusions-These data support the association of cerebral vascular disease with previous C pneumoniae infection and the association of stroke and transient cerebral ischemia with recrudescence of infection. (Stroke. 1998;29:404-410.)

The in vitro activity of BAY 12-8039, a new fluoroquinolone, was studied in comparison with those of ciprofloxacin, trovafloxacin (CP 99,219), cefpodoxime, and amoxicillin-clavulanate against gram-negative, grampositive, and anaerobic bacteria. Its activity against mycobacteria and chlamydia was also investigated. BAY 12-8039 was active against members of the family Enterobacteriaceae (MIC at which 90% of strains tested were inhibited [MIC 90 s] <1 g/ml, except for Serratia spp. MIC 90 2 g/ml), Neisseria spp. (MIC 90 s, 0.015 g/ml), Haemophilus influenzae (MIC 90 , 0.03 g/ml), and Moraxella catarrhalis (MIC 90 , 0.12 g/ml), and these results were comparable to those obtained for ciprofloxacin and trovafloxacin. Against Pseudomonas aeruginosa, the quinolones were more active than the ␤-lactam agents but BAY-12-8039 was less active than ciprofloxacin. Strains of Stenotrophomonas maltophilia were fourfold more susceptible to BAY 12-8039 and trovafloxacin (MIC 90 s, 2 g/ml) than to ciprofloxacin. BAY 12-8039 was as active as trovafloxacin but more active than ciprofloxacin against Streptococcus pneumoniae (MIC 90 , 0.25 g/ml) and methicillin-susceptible Staphylococcus aureus (MIC 90 s, 0.12 g/ml). The activity of BAY 12-8039 against methicillin-resistant S. aureus (MIC 90 , 2 g/ ml) was lower than that against methicillin-susceptible strains. BAY 12-8039 was active against anaerobes (MIC 90 s < 2 g/ml), being three-to fourfold more active against Bacteroides fragilis, Prevotella spp., and Clostridium difficile than was ciprofloxacin. Against Mycobacterium tuberculosis, BAY 12-8039 exhibited activity comparable to that of rifampin (MICs < 0.5 g/ml). Against Chlamydia trachomatis and Chlamydia pneumoniae BAY 12-8039 was more active (MICs < 0.12 g/ml) than either ciprofloxacin or erythromycin and exhibited a greater lethal effect than either of these two agents. The protein binding of BAY 12-8039 was determined at 1 and 5 g/ml as 30 and 26.4%, respectively. The presence of human serum (at 20 or 70%) had no marked effect on the in vitro activity of BAY 12-8039.

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