When growing bacteria are exposed to bactericidal concentrations of antibiotics, the sensitivity of the bacteria to the antibiotic commonly decreases with time, and substantial fractions of the bacteria survive. Using Escherichia coli CAB1 and antibiotics of five different classes (ampicillin, ciprofloxacin, rifampin, streptomycin, and tetracycline), we examine the details of this phenomenon and, with the aid of mathematical models, develop and explore the properties and predictions of three hypotheses that can account for this phenomenon: (i) antibiotic decay, (ii) inherited resistance, and (iii) phenotypic tolerance. Our experiments cause us to reject the first two hypotheses and provide evidence that this phenomenon can be accounted for by the antibiotic-mediated enrichment of subpopulations physiologically tolerant to but genetically susceptible to these antibiotics, phenotypic tolerance. We demonstrate that tolerant subpopulations generated by exposure to one concentration of an antibiotic are also tolerant to higher concentrations of the same antibiotic and can be tolerant to antibiotics of the other four types. Using a mathematical model, we explore the effects of phenotypic tolerance to the microbiological outcome of antibiotic treatment and demonstrate, a priori, that it can have a profound effect on the rate of clearance of the bacteria and under some conditions can prevent clearance that would be achieved in the absence of tolerance.When dividing bacteria are exposed to bactericidal concentrations of antibiotics, the density of viable cells does not decline exponentially. During exposure to antibiotics, the rate of mortality of bacteria decreases, and a substantial fraction of bacteria may survive and even start to grow again. This decrease in mortality has been observed for virtually all antibiotics used clinically and for many different species of bacteria (7-9, 12, 15-18, 27, 30, 32). We investigate this phenomenon by combining a population dynamic analysis with in vitro experiments.With the aid of mathematical models, we develop these three hypotheses to account for the decrease in bacterial mortality: (i) antibiotic decay (since the efficacy of antibiotics increases with their concentration, a decay in the effective concentration of the antibiotics leads to a decrease in mortality), (ii) inherited resistance (an ascent of genetically resistant mutants decreases the mortality of the total bacterial population), and (iii) phenotypic tolerance (the bacterial population, though genetically homogeneous, is physiologically heterogeneous with respect to its susceptibility, which during antibiotic exposure leads to an enrichment of the fraction of phenotypically tolerant bacteria and thus a decrease in the overall bacterial mortality).We investigate this phenomenon in vitro, using Escherichia coli and five classes of antibiotics (ciprofloxacin, ampicillin, rifampin, streptomycin, and tetracycline).We present evidence against the first two of these hypotheses and in support of the third hypothesis (phenot...
For many bacterial infections, noninherited mechanisms of resistance are responsible for extending the term of treatment and in some cases precluding its success. Among the most important of these noninherited mechanisms of resistance is the ability of bacteria to form biofilms. There is compelling evidence that bacteria within biofilms are more refractory to antibiotics than are planktonic cells. Not so clear, however, is the extent to which this resistance can be attributed to the structure of biofilms rather than the physiology and density of bacteria within them. To explore the contribution of the structure of biofilms to resistance in a quantitative way, we developed an assay that compares the antibiotic sensitivity of bacteria in biofilms to cells mechanically released from these structures. Our method, which we apply to Escherichia coli and Staphylococcus aureus each with antibiotics of five classes, controls for the density and physiological state of the treated bacteria. For most of the antibiotics tested, the bacteria in biofilms were no more resistant than the corresponding populations of planktonic cells of similar density. Our results, however, suggest that killing by gentamicin, streptomycin, and colistin is profoundly inhibited by the structure of biofilms; these drugs are substantially more effective in killing bacteria released from biofilms than cells within these structures.
These data demonstrate that integron-mediated antibiotic resistance is common among diverse Salmonella serovars, many of them rare. In addition, SGI1 is not limited to Salmonella enterica Typhimurium DT104 or other commonly isolated serovars.
To determine effects of exposure of parental animals to antibiotics on antibiotic resistance in bacteria of offspring, sows were either treated or not treated with oxytetracycline prior to farrowing and their pigs were challenged with Salmonella enterica Typhimurium and treated or not treated with oxytetracycline and apramycin. Fecal Escherichia coli were obtained from sows, and E. coli and salmonella were recovered from pigs. Antibiotic resistance patterns of isolates were determined using a minimum inhibitory concentration (MIC) analysis. Polymerase chain reaction (PCR) and electroporation were used to characterize the genetic basis for the resistance and to determine the location of resistance genes. Treatments had little effect on resistance of the salmonella challenge organism. The greatest resistance to apramycin occurred in E. coli from pigs treated with apramycin and whose sows had earlier exposure to oxytetracycline. Resistance to oxytetracycline was consistently high throughout the study in isolates from all pigs and sows; however, greater resistance was noted in pigs nursing sows that had previous exposure to that drug. The aac(3)-IV gene, responsible for apramycin resistance, was found in approximately 90% of apramycin-resistant isolates and its location was determined to be on plasmids. Several resistant E. coli bio-types were found to contain the resistance gene. These results indicate that resistance to apramycin and oxytetracycline in E. coli of pigs is affected by previous use of oxytetracycline in sows.
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