Foreign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associated risk factors were collected before and after traveling. A total of 105 volunteers were enrolled. Four of them did not complete the study, and one participant carried ESBL-producing Escherichia coli before travel. Twenty-four of 100 participants with negative pretravel samples were colonized with ESBL-producing Escherichia coli after the trip. All strains produced CTX-M enzymes, mostly CTX-M-15, and some coproduced TEM or SHV enzymes. Coresistance to several antibiotic subclasses was common. Travel to India was associated with the highest risk for the acquisition of ESBLs (88%; n ‫؍‬ 7). Gastroenteritis during the trip was an additional risk factor (P ‫؍‬ 0.003). Five of 21 volunteers who completed the follow-up after 6 months had persistent colonization with ESBLs. This is the first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing Enterobacteriaceae. Considering the high acquisition rate of 24%, it is obvious that global efforts are needed to meet the emergence and spread of CTX-M enzymes and other antimicrobial resistances.

Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenes exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (E max ) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.The MIC is the most commonly used parameter to describe the efficacy of an antibacterial agent against a bacterial strain. This is an in vitro measure reflecting the efficacy of a constant antibiotic exposure to a specified bacterial inoculum after an incubation period of 16 to 20 h (19). The MIC is an estimate of the susceptibility of a bacterial strain to an antibiotic that can guide the choice of appropriate antibiotic treatment in the clinical setting. However, it is not an optimal pharmacodynamic (PD) marker since it reflects only a point estimate of the effect and does not take the time course of the effect into account. Nevertheless, the pharmacokinetic (PK)/PD relationship for antibiotics has generally been characterized by using point estimates of the pharmacodynamics (e.g., the bacterial load after 24 h of exposure) and the pharmacokinetics. This approach has led to the classification of the antibacterial effect being dependent either on the antibiotic exposure (the maximum concentration in serum/MIC or the area under the concentration-time curve/MIC) or on the time that the antibiotic concentration is kept above the MIC (4, 18). The design of dosing schedules may, however, be further optimized if it is based on models that take the whole time course of the PK/PD relation, i.e., the time cour...

The sub-MIC effects (SMEs) and the postantibiotic sub-MIC effects (PA SMEs) of vancomycin, roxithromycin, and sparfloxacin for Streptococcus pyogenes and Streptococcus pneumoniae and of amikacin for Escherichia coli and Pseudomonas aeruginosa were investigated. A postantibiotic effect was induced by exposing strains to 10x the MIC of the antibiotic for 2 h in vitro. After the induction, the exposed cultures were washed to eliminate the antibiotics. Unexposed controls were treated similarly. Thereafter, the exposed cultures (PA SME) and the controls (SME) were exposed to different subinhibitory concentrations (0.1, 0.2, and 0.3 x the MIC) of the same drug and growth curves for a period of 24 h were compared. In general, the PA SMEs were much more pronounced than the SMEs. However, for amikacin and E. coli the SME of 0.2 and 0.3 x the MIC also had an initial bactericidal effect. The longest PA SMEs were demonstrated for the combinations with the most pronounced killing during the induction and for the combinations which exhibited the longest PAEs.In the early 1940s, the dosage schedules devised for penicillin therapy were based on the assumption that drug concentrations must be maintained above the MIC. This assumption was based on previous experiments with the sulfonamides (1, 26). However, a few years after the introduction of penicillin, it was shown both in animal experiments and in clinical studies that a discontinuous penicillin therapy was as effective as a continuous one, even if the concentrations in serum had fallen under the MIC (4, 26, 28). At that time, Eagle et al. showed, both in vitro and in a thigh infection model in mice, that there was a lag phase before regrowth of bacteria after a first challenge of penicillin (5, 6). This concept aroused new interest in the 1970s and was named the postantibiotic effect (PAE) (3,14,33). The PAE has been extensively studied both in vitro and in vivo and has been cited as one explanation for the success of intermittent dosing regimens (3, 32). However, in most antibioticbacterium combinations the sum of the time that the drug concentration is above the MIC and the PAE does not cover the whole dosing interval. Also, in the in vivo situation, a suprainhibitory concentration of a drug will always be followed by subinhibitory concentrations (sub-MICs).We have shown earlier that subinhibitory antibiotic concentrations may have different effects on bacteria exposed previously to suprainhibitory antibiotic concentrations (postantibiotic sub-MIC effect [PA SME]), compared with the effects on bacteria not previously exposed to antibiotics (sub-MIC effect [SME]) (18,20). In most of the investigated combinations with P-lactam antibiotics, we found a pronounced difference in time between the PA SME and the SME, with two exceptions. In the combinations with no PAE, neither a PA SME nor an SME was found, and in the combination of imipenem with Pseudomonas aeruginosa, both a long PA SME and an SME were seen (20).The aim of this study was to investigate the occurrence of PA SME...

The pharmacodynamic effects of subinhibitory concentrations of different ,B-lactam antibiotics were investigated. A postantibiotic effect (PAE) was induced for different bacterial species by exRosure to lOx MIC of several ,B-lactam antibiotics for 2 h in vitro. The antibiotic-bacterial combinations used in this study were imipenemPseudomonas aeruginosa, benzylpenicillin-Streptococcus pneumonae and -Streptococcus pyogenes, cgefcanel-S. pyogenes, ampicillin-Escherichia coli, and piperacillin-E. coli. After the induction of the PAE, the exposed cultures as well as the unexposed controls were washed and diluted. Thereafter, the cultures in the postantibiotic phase (PA phase) and the cultures not previously treated with antibiotics were exposed to 0.1, 0.2, and 0.3x MIC of the relevant drug and the growth curves were compared. When bacteria in the PA phase were exposed to sub-MICs, a substantial prolongation of the time before regrowth was demonstrated, especially in antibioticbacterial combinations for which a PAE wqs found. In contrast, sub-MICs on cultures not previously exposed to suprainhibitory antibiotic concentrations yielded oidy a slight reduction in growth rate compared with the controls. Thus, it seems important to distinguish the direct effects of sub-MICs on bacteria not previously exposed to suprainhibitory concentrations from the effects of sub-MICs on bacteria in the PA phase.The effects on bacteria of subinhibitory antibiotic concentrations (sub-MICs) were noted early in the antibiotic era. In 1944, Eagle and Musselman reported a temporary inhibition of the growth of spirochetes after exposure to sub-MICs of penicillin in vitro (10). Clinical experience at that time also revealed satisfactory results when patients with pneumococcal pneumonia were treated with low doses of penicillin which could hardly have yielded concentrations in serum above the MIC (38). Furthermore, Eagle and coworkers showed, both in vitro and in a rabbit model, that grampositive bacteria exposed to a suprainhibitory concentration of penicillin did not return to a growth phase immediately after the concentration in serum had fallen under the MIC (9, 11). This effect was later named the postantibiotic effect (PAE) and is one of many explanations for the success of intermittent dosage with antibiotics (7). Another factor of importance for the success of discontinuous antibiotic dosing is the function of a normal host defense system. For example, it does not seem to be necessary to keep the level of P-lactam antibiotics in serum above the MIC to clear an infection in immunocompetent animals, whereas several studies using neutropenic animals have shown the importance of maintaining levels of P-lactam antibiotics in serum above the MIC in order to avoid regrowth of gram-negative bacteria (3,14,33). One reason for the difference between immunocompetent and neutropenic animals is that bacteri,a exposed to sub-MICs in immunocompetent animals are more susceptible to phagocytic cell functions (13,19,24,26,41). Sub-MICs can also exert a d...

The bactericidal activities of vancomycin against two reference strains and two clinical isolates of Staphylococcus aureusand Staphylococcus epidermidis were studied with five different concentrations ranging from 2× to 64× the MIC. The decrease in the numbers of CFU at 24 h was at least 3 log10CFU/ml for all strains. No concentration-dependent killing was observed. The postantibiotic effect (PAE) was determined by obtaining viable counts for two of the reference strains, and the viable counts varied markedly: 1.2 h for S. aureus and 6.0 h for S. epidermidis. The determinations of the PAE, the postantibiotic sub-MIC effect (PA SME), and the sub-MIC effect (SME) for all strains were done with BioScreen C, a computerized incubator for bacteria. The PA SMEs were longer than the SMEs for all strains tested. A newly developed in vitro kinetic model was used to expose the bacteria to continuously decreasing concentrations of vancomycin. A filter prevented the loss of bacteria during the experiments. One reference strain each of S. aureus andS. epidermidis and two clinical isolates of S. aureus were exposed to an initial concentration of 10× the MIC of vancomycin with two different half-lives (t 1/2s): 1 or 5 h. The post-MIC effect (PME) was calculated as the difference in time for the bacteria to grow 1 log10 CFU/ml from the numbers of CFU obtained at the time when the MIC was reached and the corresponding time for an unexposed control culture. The difference in PME between the strains was not as pronounced as that for the PAE. Furthermore, the PME was shorter when a t 1/2 of 5 h (approximate terminal t 1/2 in humans) was used. The PMEs at t 1/2s of 1 and 5 h were 6.5 and 3.6 h, respectively, for S. aureus. The corresponding figures for S. epidermidis were 10.3 and less than 6 h. The shorter PMEs achieved with at 1/2 of 5 h and the lack of concentration-dependent killing indicate that the time above the MIC is the parameter most important for the efficacy of vancomycin.