Structure-activity correlation experiments demonstrated that the fine structure of 3-oxo-C 12 -HSL, the HSL backbone, and side chain length are required for maximal activity. These data suggest that Pseudomonas 3-oxo-C 12 -HSL specifically promotes induction of apoptosis, which may be associated with 3-oxo-C 12 -HSL-induced cytotoxicity in macrophages and neutrophils. Our data suggest that the quorum-sensing molecule 3-oxo-C 12 -HSL has critical roles in the pathogenesis of P. aeruginosa infection, not only in the induction of bacterial virulence factors but also in the modulation of host responses.

To better evaluate patient contribution in antibiotic use, we questioned 5379 subjects from 9 countries. Antibiotics are perceived as strong, efficient drugs, but they are believed to undermine immunity. Interviewees believe that most respiratory infections, except the common cold, require antibiotic therapy, and 11% of them had to exaggerate their symptoms to get an antibiotic prescription from their physician. About 1 patient in 4 saved part of the antibiotic course for future use. Sixty-nine percent of the patients claimed to have taken the course until the end (United Kingdom, 90%; Thailand, 53%), and 75% claimed that they actually took all the daily doses. In all countries, it was possible to get antibiotics from a pharmacist without a medical prescription. This study shows that patients exert pressure on their doctors to get antibiotics and should allow a design for precise educational action aimed at the public for better control of antibiotic use in the community.

While meropenem MICs were strongly influenced by the presence or absence of the MexAB-OprM efflux pump in both OprD-proficient and -deficient strain backgrounds, MICs of imipenem and of ER-35786 remained unchanged, demonstrating that meropenem is a substrate of MexAB-OprM but not imipenem and ER-35786. In vitro, all three carbapenems selected loss of OprD as a first mechanism of resistance. However, in an OprD-deficient background, meropenem was able to select MexAB-OprM overproducers as a secondary resistance mechanism, while ER-35786 selected a mutant cross-resistant to sparfloxacin and cefpirome.

Resistance mechanisms selected after in vitro exposure to 12 quinolones were analyzed for Pseudomonas aeruginosa. Efflux-type mutants were predominant. Quinolones differed in their ability to select a particular efflux system. While the newer fluoroquinolones favored the MexCD-OprJ system, the older quinolones selected exclusively the MexEF-OprN or MexAB-OprM systems. A protonable C-7 substituent in combination with a C-6 fluorine atom is a structural determinant of quinolones involved in efflux pump substrate specificity.

The relative efficacy of different aminoglycosides or of different dosage schedules of the same aminoglycoside should be quantitated and related to relative toxicity. Quantitative experimental indicators of efficacy should not only include MIC and MBC, but also the postantibiotic effect in vitro and in vivo, the emergence of resistance in in-vitro and in-vivo models, and the relationship between plasma concentration profiles and efficacy. Parameters of clinical efficacy are to be related to pharmacokinetic parameters such as the ratio between the peak serum concentration and the MIC.Toxicity in clinical trials should be assessed by the most sensitive methods available. Experimental and clinical studies have shown cortical uptake to be a sensitive indicator of renal toxicity. As far as ototoxicity is concerned endolymph and perilymph pharmacoldnetics are not dearly related. Chnical ototoxicity should be assessed by sensitive methods, such as high frequency tone audiometry. Finally, risk factors for nephrotoxicity and ototoxicity (e.g., duration of treatment, associated nephrotoxk drugs, dehydration) should be assessed in the evaluation of clinical trials.