Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-Resistant<i>Escherichia coli</i>

Olofsson, Sara K.; Geli, Patricia; Andersson, Dan I.; Cars, Otto

doi:10.1128/aac.49.12.5081-5091.2005

Cited by 35 publications

(27 citation statements)

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“…Hence, it would be useful to be able to predict clinical efficacy from in vitro PK/PD analysis and the PK profile of human ELF. Moreover, the in vitro PD model has been reported to be useful because it can simulate a variety of PK profiles which, for example, varied t 1/2 with a fixed C max (10,24). These PK profiles were very effective for determining the dominant PK/PD parameter correlated with antibacterial activity.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

Homma

Hori

Ohshiro

et al. 2010

Antimicrob Agents Chemother

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The pharmacokinetic (PK)/pharmacodynamic (PD) parameters and the antibacterial activity of S-013420, a novel bicyclolide, against Haemophilus influenzae and Streptococcus pneumoniae, including macrolide-resistant isolates, were investigated using an in vitro PD model. Various time-concentration curves were artificially constructed by modifying the PK data obtained in phase I studies. The activity against H. influenzae was evaluated using two parameters, that is, the area above the killing curve (AAC) and the viable cell reduction at 24 h. The relationships between the antibacterial activity of S-013420 and the three PK/PD parameters were investigated by fitting the data to the sigmoid maximum effective concentration model In antimicrobial chemotherapy, the pharmacokinetic (PK)/ pharmacodynamic (PD) concept has recently been used during drug development to determine susceptibility breakpoints, predict clinical efficacy, and optimize the antimicrobial regimen (1, 4, 13). Generally, antimicrobials can be categorized according to the dominant parameter of three PK/PD parameters correlated with antibacterial activity. These three parameters (1) are the area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC, the peak concentration (C max )/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state PK conditions (%T MIC ). Nonclinical PK/PD characterizations of antimicrobials using in vitro PD models or in vivo infection models have been reported (2,5,26,29). In general, AUC 0-24 /MIC is the dominant PK/PD parameter for macrolides, ketolides, and quinolones, while C max /MIC is the main parameter for quinolones and aminoglycosides and %T MIC is that for ␤-lactams (1, 4). Overall, nonclinical PK/PD data have agreed well with data obtained for infected patients, and a PK/PD evaluation would be helpful for cutting costs, addressing ethical issues, and shortening the duration of clinical trials (1, 4).Community-acquired respiratory tract infections (RTIs), such as community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and acute otitis media, are among the most common infectious diseases for which oral antibiotics are prescribed in primary clinical settings and are mainly caused by Streptococcus pneumoniae and Haemophilus influenzae (6). The macrolide antimicrobials, including clarithromycin and azithromycin, are often used for the treatment of community-acquired RTIs. However, the decreased susceptibility of S. pneumoniae to macrolide agents is a key problem worldwide. Recent reports have suggested that pneumococcal macrolide resistance rates were about 35% in some regions (7,14,23). In S. pneumoniae, two main mechanisms of macrolide resistance were reported, i.e., active efflux due to mef genes and ribosomal modification mediated by erm genes (11). S-013420 (EDP-420, EP-013420) is a novel bicyclolide (bridged bicyclic macrolide) that is characterized by a 6,11-O-bridged structure discovered by Enanta Pharmaceuticals, Inc. ...

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Section: Discussionmentioning

confidence: 99%

In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

Homma

Hori

Ohshiro

et al. 2010

Antimicrob Agents Chemother

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“…Our model suggests that if first-step or intermediate-resistance mutants are already present at the onset of or evolve during treatment, the likelihood of high-level clinical resistance emerging also declines with antibiotic dose. This prediction is supported by in vitro (48,59,66,67) and animal model experiments (52,68). Although not responsible for mortality, there are three compelling reasons to control the ascent of resistance in acute self-limiting infections: to minimize (i) the term of morbidity, (ii) the reservoir of resistant commensal and potentially invasive bacteria in the treated host, and (iii) the extent of transmission of resistant bacteria into the community.…”

Section: Nb 1 Amentioning

confidence: 92%

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections

Ankomah

Levin

2014

Proc. Natl. Acad. Sci. U.S.A.

120

139

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The successful treatment of bacterial infections is the product of a collaboration between antibiotics and the host's immune defenses. Nevertheless, in the design of antibiotic treatment regimens, few studies have explored the combined action of antibiotics and the immune response to clearing infections. Here, we use mathematical models to examine the collective contribution of antibiotics and the immune response to the treatment of acute, self-limiting bacterial infections. Our models incorporate the pharmacokinetics and pharmacodynamics of the antibiotics, the innate and adaptive immune responses, and the population and evolutionary dynamics of the target bacteria. We consider two extremes for the antibiotic-immune relationship: one in which the efficacy of the immune response in clearing infections is directly proportional to the density of the pathogen; the other in which its action is largely independent of this density. We explore the effect of antibiotic dose, dosing frequency, and term of treatment on the time before clearance of the infection and the likelihood of antibiotic-resistant bacteria emerging and ascending. Our results suggest that, under most conditions, high dose, full-term therapy is more effective than more moderate dosing in promoting the clearance of the infection and decreasing the likelihood of emergence of antibiotic resistance. Our results also indicate that the clinical and evolutionary benefits of increasing antibiotic dose are not indefinite. We discuss the current status of data in support of and in opposition to the predictions of this study, consider those elements that require additional testing, and suggest how they can be tested.population dynamics | immunology T he goals of antibiotic treatment of bacterial infections are straightforward and interrelated: to maximize the likelihood and rate of cure, to minimize the toxic and other deleterious side effects of treatment, and to minimize the likelihood of resistance emerging during the course of therapy. How does one choose the most effective antibiotic(s) for a given infection and determine its optimum dose, frequency, and term of administration to achieve these goals?One answer has been to combine in vitro studies of the pharmacodynamics (PD) of the antibiotics and bacteria and the in vivo pharmacokinetics (PK) of the antibiotics in treated patients or model organisms (1, 2). Central to this "rational" (as opposed to purely empirical) approach to antibiotic treatment are PK/PD indices. Although there have been efforts to develop more comprehensive measures of the relationship between the concentration of antibiotics and rate of bacterial growth (e.g., see refs. 3-5), in practice the lowest antibiotic concentration required to prevent the in vitro growth of the bacteria [the minimum inhibitory concentration (MIC)] is the sole pharmacodynamic parameter used for these indices (6). Depending on the drug, one of three PK parameters that quantify drug availability is combined with the MIC to generate these PK/PD indices: (i) the r...

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“…Another method of studying resistance selection is through the use of competition assays that use strains with different drug susceptibilities. The different populations can be measured using a discriminative marker; the presence of a mutation in the arabinose gene results in a different colony color on a certain agar and allows for the simple identification of each strain in a mixed culture [34,44]. Measurement of resistance development in the clinical setting is, as for efficacy studies, limited by discontinuous end points.…”

Section: Resistance Prevention Studiesmentioning

confidence: 99%

Optimizing Drug Exposure to Minimize Selection of Antibiotic Resistance

Olofsson

Cars

2007

Clinical Infectious Diseases

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173

127

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The worldwide increase in antibiotic resistance is a concern for public health. The fact that the choice of dose and treatment duration can affect the selection of antibiotic-resistant mutants is becoming more evident, and an increased number of studies have used pharmacodynamic models to describe the drug exposure and pharmacodynamic breakpoints needed to minimize and predict the development of resistance. However, there remains a lack of sufficient data, and future work is needed to fully characterize these target drug concentrations. More knowledge is also needed of drug pharmacodynamics versus bacteria with different resistance mutations and susceptibility levels. The dosing regimens should exhibit high efficacy not only against susceptible wild-type bacteria but, preferably, also against mutated bacteria that may exist in low numbers in "susceptible" populations. Thus, to prolong the life span of existing and new antibiotics, it is important that dosing regimens be carefully selected on the basis of pharmacokinetic and pharmacodynamic properties that prevent emergence of preexisting and newly formed mutants. ANTIBIOTIC RESISTANCEAntibiotic resistance has become a serious global problem and affects almost every bacterial species for which treatment with antibiotics is available. Resistance to multiple antibiotics has developed among many common pathogens, such as staphylococci, pneumococci, Pseudomonas organisms, and extended-spectrum b-lactamase (ESBL)-producing strains of Enterobacteriaceae, and the resistance problem is steadily increasing worldwide. Consequently, the therapeutic options for the treatment of some infections are limited, especially in developing countries, where second-and third-line antibiotics are unavailable or unaffordable. Infectious diseases cause 111 million deaths annually [1], and treatment failure caused by antibiotic-resistant bacteria is a contributing factor in these deaths, although the quantitative burden of antibiotic resistance is not certain.The development and spread of antibiotic-resistant bacteria are affected by several factors. Some factors are bacteria specific, such as the mutation rate, the transmission rate, the biological fitness costs, and the ability to compensate for such costs. Other factors of major importance in the emergence of resistance are the volume and quality of antibiotic use, including prescription when there is no clinical indication, over-thecounter sales or sales by drug vendors, inappropriate drug choice, and suboptimal dosing [2,3]. Dissemination of antibiotic resistance is also influenced by environmental factors in the community and hospitals. Direct or indirect person-to-person transmission is affected by population density and hospital structure and significantly increases in association with poor hygiene. MUTATION RATEIn a bacterial cell, spontaneous mutations normally occur at a rate of mutations/bp/generation dur- Ϫ9 Ϫ1010 -10 ing DNA replication [4,5]. In contrast to the mutation rate, the mutation frequency measures all of the mutant...

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Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-ResistantEscherichia coli

Cited by 35 publications

References 46 publications

In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections

Optimizing Drug Exposure to Minimize Selection of Antibiotic Resistance

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