It has been widely assumed that the ecological function of antibiotics in nature is fighting against competitors. This made them a good example of the Darwinian struggle-for-life in the microbial world. Based on this idea, it also has been believed that antibiotics, even at subinhibitory concentrations, reduce virulence of bacterial pathogens. Herein, using a combination of genomic and functional assays, we demonstrate that specific antibiotics (namely tobramycin, tetracycline, and norfloxacin) at subinhibitory concentrations trigger expression of determinants influencing the virulence of the major opportunistic bacterial pathogen Pseudomonas aeruginosa. All three antibiotics induce biofilm formation; tobramycin increases bacterial motility, and tetracycline triggers expression of P. aeruginosa type III secretion system and consequently bacterial cytotoxicity. Besides their relevance in the infection process, those determinants are relevant for the ecological behavior of this bacterial species in natural, nonclinical environments, either by favoring colonization of surfaces (biofilm, motility) or for fighting against eukaryotic predators (cytotoxicity). Our results support the notion that antibiotics are not only bacterial weapons for fighting competitors but also signaling molecules that may regulate the homeostasis of microbial communities. At low concentrations, they can even be beneficial for the behavior of susceptible bacteria in natural environments. This is a complete change on our vision on the ecological function of antibiotics with clear implications both for the treatment of infectious diseases and for the understanding of the microbial relationships in the biosphere. environment ͉ hormesis ͉ signals ͉ antibiotics ͉ Pseudomonas aeruginosa

High antibiotic use selected for commensals with highly increased resistance and a slight increase in mutation frequency.

An in vitro kinetic model was used to study the relation between pharmacokinetic and pharmacodynamic (PK-PD) parameters for antimicrobial effect, e.g., the time above MIC (T>MIC), maximum concentration in serum (C max ), and area under the concentration-time curve (AUC). Streptococcus pyogenes and Escherichia coli were exposed to cefotaxime, and the activity of amoxicillin against four strains of Streptococcus pneumoniae with different susceptibilities to penicillin was studied. The drug elimination rate varied so that the T>MIC ranged from 20 to 100% during 24 h, while the AUC and/or the initial concentration (C max ) were kept constant. For S. pyogenes and E. coli, the maximal antimicrobial effect (E max ) at 24 h occurred when the antimicrobial concentration exceeded the MIC for 50 and 80% of the strains tested, respectively. The penicillin-susceptible pneumococci (MIC, 0.03 mg/liter) and the penicillin-intermediate strain (MIC, 0.25 mg/liter) showed maximal killing by amoxicillin at a T>MIC of 50%. For a strain for which the MIC was 2 mg/liter, C max needed to be increased to achieve the E max . Under the condition that C max was 10 times the MIC, E max was obtained at a T>MIC of 60%, indicating that C max , in addition to T>MIC, may be an important parameter for antimicrobial effect on moderately penicillin-resistant pneumococci. For the strain for which the MIC was 4 mg/liter, the reduction of bacteria varied from ؊0.4 to ؊3.6 log 10 CFU/ml at a T>MIC of 100%, despite an initial antimicrobial concentration of 10 times the MIC. Our studies have shown that the in vitro kinetic model is a useful complement to animal models for studying the PK-PD relationship for antimicrobial effect of antibiotics.The optimal dosing regimen for antibiotics is still not fully understood. Obtaining clinical and microbiological efficacy is essential, but dosing regimens must also be tailored to minimize the risk for emergence of antibiotic-resistant strains. The prevailing method for determination of bacterial susceptibility, the MIC, is only a rough measure of antimicrobial activity. It gives no information about the time course or whether the bactericidal effect is dependent on drug concentration. Many additional factors need to be studied in order to increase knowledge about optimal dosing regimens, e.g., the relation between pharmacokinetic and pharmacodynamic parameters (PK-PD), interactions with the immune system of the host, and pharmacological determinants for selection of resistance at the site of infection and in the normal flora.A number of reasons, e.g., economical and ethical, limit the possibilities for dose finding in clinical studies in which the PK-PD relationship can be defined for optimal efficacy. Another problem is that the pharmacokinetic parameters are interdependent; i.e., an increased dose leads to a higher maximum concentration (C max ) and a larger area under the concentration-time curve (AUC), as a well as a longer time above the MIC (TϾMIC) (7,8,13). Studies of animal and in vitro models give the pos...

Streptococcus pneumoniae is the most significant bacterial cause of community-acquired respiratory tract infections (23). During the last decade, the spread of penicillin nonsusceptible pneumococci with increased MICs has created clinically significant treatment problems, especially in infections against which therapeutic concentrations are difficult to achieve, such as meningitis (1,(15)(16)(17)(18)28). Clinical and animal studies indicate, however, that by optimizing the dosing regimen, it may still be possible in many cases to use penicillin for treatment of S. pneumoniae with decreased susceptibility (3-5, 8-10, 12-14, 25). Dosing regimens should, however, be optimized not only to obtain a maximal antibacterial effect but also to reduce the risk for the emergence of resistance (2,19,24). Little is known about the selective properties of different antibiotic regimens in a mixed culture of bacteria with different antibiotic susceptibilities. The normal nasopharyngeal flora of patients may be simultaneously colonized with different types of S. pneumoniae having a variable resistance pattern. A certain dosage regimen could select more resistant strains even if these at the time constitute a minority for the original population (11,21,26,27). The aim of the present investigation was to use an in vitro kinetic model to study the selective effects of different concentrations of benzylpenicillin on a culture containing a mixture of 90% penicillin-susceptible, 9% penicillin-intermediate, and 1% penicillin-resistant S. pneumoniae strains.(This study was presented in part at the 40th InterscienceConference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, on 17 to 20 September 2000.) MATERIALS AND METHODS Antibiotic.Benzylpenicillin was provided by AstraZeneca, Södertälje, Sweden. The antibiotic was obtained as a reference powder with known potency and dissolved in distilled water prior to each experiment.Bacterial strains. Three clinical strains of S. pneumoniae belonging to serotype 6B obtained from the Department of Microbiology, University Hospital, Reykjavik, Iceland, were used in the study: S. pneumoniae A 2000 (PSP), S. pneumoniae 9506 (PIP), and S. pneumoniae BCC-67 (PRP).Determination of MICs. The MICs for the three strains of S. pneumoniae were determined in fluid media by a macrodilution technique in duplicate on different occasions according to the National Committee for Clinical Laboratory Standards. Twofold serial dilutions of benzylpenicillin were added to broth and inoculated with a final inoculum of 10 5 CFU of the test strain per ml and incubated at 37°C in 5% CO 2 for 20 h. The MIC was defined as the lowest concentration of the antibiotic allowing no visible growth. The MICs of erythromycin were determined with E-test (Biodisk, Solna, Sweden).The MICs of penicillin were 0.031, 0.25, and 8 mg/liter, respectively. The PSP strain was erythromycin resistant (MIC Ͼ 128 mg/liter), whereas the two other strains were susceptible to erythromycin (MIC Ͻ 0.03 mg/liter).Concentrations of benzylpenicill...