Effect of Dosing and Dosing Frequency on the Efficacy of Ceftizoxime and the Emergence of Ceftizoxime Resistance during the Early Development of Murine Abscesses Caused by
            <i>Bacteroides fragilis</i>
            and
            <i>Enterobacter cloacae</i>
            Mixed Infection

Stearne, Lorna E. T.; Goessens, W. H. F.; Mouton, Johan W.; Gyssens, Inge C.

doi:10.1128/aac.01486-06

Cited by 27 publications

(20 citation statements)

References 36 publications

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“…Our results also suggest that if at the onset of treatment all of the target bacteria are susceptible to the antibiotic, the likelihood of de novo resistance evolving will decline with the dose of the drug. There is support for this prediction from in vitro experiments (47,49,(56)(57)(58)(59), animal models (60,61), and human studies (62)(63)(64). By rapidly reducing the density of the infecting bacteria, …”

Section: Resultsmentioning

confidence: 93%

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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Section: Resultsmentioning

confidence: 93%

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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“…Identification of the pharmacokinetic/pharmacodynamic (PKPD) index that best predicts a successful outcome became a cornerstone of optimization of antimicrobial therapy (2,16,21). However, PKPD target values may vary between antibiotics and pathogens (2, 3) and may not be universal for all infections (27) and types of outcomes (44,59). For example, severe infections, such as endocarditis, infections of prostheses, and ventilator-associated pneumonia are known to have a high density of bacteria, which is associated with a higher mortality (25,47,54,60).…”

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confidence: 99%

Attenuation of Colistin Bactericidal Activity by High Inoculum of Pseudomonas aeruginosa Characterized by a New Mechanism-Based Population Pharmacodynamic Model

Bulitta

Yang

Yohonn

et al. 2010

Antimicrob Agents Chemother

119

130

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Colistin is increasingly being utilized against Gram-negative pathogens, including Pseudomonas aeruginosa, resistant to all other antibiotics. Since limited data exist regarding killing by colistin at different initial inocula (CFUo), we evaluated killing of Pseudomonas aeruginosa by colistin at several CFUo and developed a mechanism-based mathematical model accommodating a range of CFUo. In vitro time-kill experiments were performed using >8 concentrations up to 64 ؋ the MIC of colistin against P. aeruginosa PAO1 and two clinical P. aeruginosa isolates at CFUo of 10 6 , 10 8 , and 10 9 CFU/ml. Serial samples up to 24 h were simultaneously modeled in the NONMEM VI (results shown) and S-ADAPT software programs. The mathematical model was prospectively "validated" by additional time-kill studies assessing the effect of Ca 2؉ and Mg 2؉ on killing of PAO1 by colistin. Against PAO1, killing of the susceptible population was 23-fold slower at the 10 9 CFUo and 6-fold slower at the 10 8 CFUo than at the 10 6 CFUo. The model comprised three populations with different second-order killing rate constants (5.72, 0.369, and 0.00210 liters/h/mg). Bacteria were assumed to release signal molecules stimulating a phenotypic change that inhibits killing. The proposed mechanism-based model had a good predictive performance, could describe killing by colistin for all three studied strains and for two literature studies, and performed well in a prospective validation with various concentrations of Ca 2؉ and Mg 2؉ . The extent and rate of killing of P. aeruginosa by colistin were markedly decreased at high CFUo compared to those at low CFUo. This was well described by a mechanism-based mathematical model, which should be further validated using dynamic in vitro models.

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“…aeruginosa with meropenem (Tam et al 2007b ). AUC/MIC was the important index for preventing emergence of derepressed AmpC-resistant mutants to ceftizoxime in an Enterobacter cloacae and Bacteroides fragilis abscess model; the required magnitude value was 1,000 (Stearne et al 2007 ). For linezolid dosing with anthrax, the PK/PD index for suppressing resistant mutants was the peak/MIC ratio (Louie et al 2008 ).…”

Section: Pk/pd Targets For Resistance Suppressionmentioning

confidence: 99%

Introduction to Pharmacodynamics

Craig

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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Since the early appreciation of differences in the time course of antimicrobial activity, much has been learned about the pharmacodynamics of antimicrobials. Specifi c PK/PD indices have been identifi ed which are of major importance for effi cacy and for the prevention of the emergence of resistance. Of major importance, the magnitudes of these PK/PD indices for effi cacy have been shown to be very similar in animal infection models and human infections. Modeling has also identifi ed that there are few differences in the index magnitude with different dosing intervals, among drugs within the same antimicrobial class (providing free drug concentrations are used), with different infection sites (except occasionally for pneumonia), and among susceptible and resistant strains of the same type of bacteria. Addition studies have shown that the magnitude of indices can increase signifi cantly with a higher inoculum for S . aureus and that neutrophils have a minor enhancing effect on antimicrobial activity against Enterobacteriaceae but a more variable enhancing effect on activity against S . pneumonia for different antimicrobials. Pharmacodynamic modeling has many applications including establishing new optimal dosing regimens, developing new antimicrobials and formulations, determining susceptibility breakpoints, providing guidelines for empiric therapy, and formulary development. IntroductionAntimicrobial pharmacodynamics deals with the relationship between measures of drug exposure and the effi cacy and toxicity of antimicrobial agents. Since the early days of penicillin, researchers have been interested in determining which pharmacokinetic parameter is most important in determining microbiologic and clinical effi cacy. For example, bacterial killing of staphylococci by penicillin was much different than by streptomycin (Garrod 1948 ). The rate of killing by penicillin was not dependent on the height of the drug concentration, while streptomycin demonstrated enhanced killing at higher concentrations. Studies in mice-infection models suggested that the duration of drug exposure was the most important parameter determining in vivo therapeutic effi cacy of penicillin (Eagle et al. 1950 ). Interest in antimicrobial pharmacodynamics increased in the 1960s and 1970s when infections due to Pseudomonas aeruginosa with high MICs to multiple drugs appeared with increasing frequency (Rolinson 1973 ). This interest in antimicrobial pharmacodynamics has been further enhanced by the emergence of antimicrobial resistance to many drugs during the last 15-20 years. Time Course of Antimicrobial ActivityA major determinant of the time course of antimicrobial activity is whether the drug exhibits bactericidal activity and whether the killing is enhanced by increasing concentrations or by longer exposure times. The second major determinant is whether the drug exhibits persistent inhibition of growth that lasts after the drug exposure. There are numerous in vitro persistent effects described in the literature that usually act t...

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Effect of Dosing and Dosing Frequency on the Efficacy of Ceftizoxime and the Emergence of Ceftizoxime Resistance during the Early Development of Murine Abscesses Caused by Bacteroides fragilis and Enterobacter cloacae Mixed Infection

Cited by 27 publications

References 36 publications

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

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

Attenuation of Colistin Bactericidal Activity by High Inoculum of Pseudomonas aeruginosa Characterized by a New Mechanism-Based Population Pharmacodynamic Model

Introduction to Pharmacodynamics

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