Influence of inoculum size of Staphylococcus aureus and Pseudomonas aeruginosa on in vitro activities and in vivo efficacy of fluoroquinolones and carbapenems

Mizunaga, Shingo; Kamiyama, Tsutomu; Fukuda, Yoshiko; Takahata, Masahiro; Mitsuyama, Junichi

doi:10.1093/jac/dki163

Cited by 70 publications

(63 citation statements)

References 20 publications

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“…Since there was no washout of signal molecules or other substances, a time-kill experiment as in our study may overestimate the inoculum effect in vivo. However, several animal infection model studies showed the significance of the inoculum effect in vivo (25,38,47,60). It is important to note that the clinical relevance of the inoculum effect has rarely been demonstrated, and numerous factors, such as host defense and severity of infection, greatly influence antimicrobial effect and treatment success in patients.…”

Section: Discussionmentioning

confidence: 99%

“…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). Furthermore, an increased density of bacteria represents a greater challenge to the immune system and may result in higher bacterial toxin concentrations.…”

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confidence: 99%

“…Furthermore, an increased density of bacteria represents a greater challenge to the immune system and may result in higher bacterial toxin concentrations. In addition, bacterial killing by antibiotics has been shown to be attenuated at high initial inocula (CFUo) compared to low CFUo (9,10,47,53,67,69).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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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“…Interestingly, some other studies have shown that the in vitro efficacy of antimicrobials can depend on the size of the bacterial inoculum, with drugs being more potent against low than against high inocula (10)(11)(12). It was subsequently shown in vivo that lower antibiotic doses given in the early prepatent phase of an infection, when the pathogen burden was still low, were as effective as higher doses administered during the patent phase of infection, as characterized by overt clinical symptoms and a high bacterial burden (13)(14)(15)(16)(17).…”

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confidence: 99%

Low or High Doses of Cefquinome Targeting Low or High Bacterial Inocula Cure Klebsiella pneumoniae Lung Infections but Differentially Impact the Levels of Antibiotic Resistance in Fecal Flora

Vasseur

Laurentie

Rolland

et al. 2014

Antimicrob Agents Chemother

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The combination of efficacious treatment against bacterial infections and mitigation of antibiotic resistance amplification in gut microbiota is a major challenge for antimicrobial therapy in food-producing animals. In rats, we evaluated the impact of cefquinome, a fourth-generation cephalosporin, on both Klebsiella pneumoniae lung infection and intestinal flora harboring CTX-Mproducing Enterobacteriaceae. Germfree rats received a fecal flora specimen from specific-pathogen-free pigs, to which a CTX-M-producing Escherichia coli strain had been added. K. pneumoniae cells were inoculated in the lungs of these gnotobiotic rats by using either a low (10 5 CFU) or a high (10 9 CFU) inoculum. Without treatment, all animals infected with the low or high K. pneumoniae inoculum developed pneumonia and died before 120 h postchallenge. In the treated groups, the low-inoculum rats received a 4-day treatment of 5 mg/kg of body weight cefquinome beginning at 24 h postchallenge (prepatent phase of the disease), and the high-inoculum rats received a 4-day treatment of 50 mg/kg cefquinome beginning when the animals expressed clinical signs of infection (patent phase of the disease). The dose of 50 mg/kg targeting the high K. pneumoniae inoculum cured all the treated rats and resulted in a massive amplification of CTX-M-producing Enterobacteriaceae. A dose of 5 mg/kg targeting the low K. pneumoniae inoculum cured all the rats and averted an outbreak of clinical disease, all without any amplification of CTX-M-producing Enterobacteriaceae. These findings might have implications for the development of new antimicrobial treatment strategies that ensure a cure for bacterial infections while avoiding the amplification of resistance genes of human concern in the gut microbiota of food-producing animals.A ntimicrobial resistance is a major threat to human health, and the overuse of antibiotics in both human patients and animals is considered to be the main factor leading to the selection of resistant bacteria. It is also increasingly recognized that the gut microbiota constitutes one of the main reservoirs of resistance genes among commensal bacterial ecosystems (1-4), and that the antibiotic doses currently used in human and animal patients have not been optimized to prevent the collateral selection of antimicrobial resistance in the gut microbiota or its colonization by exogenous resistant strains (3, 5).An examination of the interactions between antibiotics, pathogens, and the commensal flora, as well as an increased understanding of the key factors governing antimicrobial activity and resistance selection, might lead to the development of strategies combining maximal efficacy with minimal impact on the commensal bacterial ecosystems (2, 6, 7). For example, recent studies demonstrated that the degree of amplification of antimicrobial resistance in the gut microbiota was directly correlated with the magnitude of the antibiotic dose, regardless of the route of administration (8, 9).Interestingly, some other studies have shown that the i...

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“…45 These results showed that the knowledge of the influence of inoculum is useful for further research, namely to assess bacterial adhesion to other biomaterials. 46,47 The biofilm structure and morphology formed on these biomaterial surfaces, over time, were also assessed by SEM. A mature biofilm with EPS production and three-dimensional mushroom-like or pillar-like structures was observed, on both biomaterial surfaces.…”

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confidence: 99%

Influence of nanohydroxyapatite surface properties on Staphylococcus epidermidis biofilm formation

et al. 2013

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Nanohydroxyapatite (nanoHA), due to its chemical properties, has appeared as an exceptionally promising bioceramic to be used as bone regeneration material. Staphylococcus epidermidis have emerged as major nosocomial pathogens associated with infections of implanted medical devices. In this work, the purpose was to study the influence of the nanoHA surface characteristics on S. epidermidis RP62A biofilm formation. Therefore, two different initial inoculum concentrations (Ci) were used in order to check if these would affect the biofilm formed on the nanoHA surfaces. Biofilm formation was followed by the enumeration of cultivable cells and by scanning electron microscopy. Surface topography, contact angle, total surface area and porosimetry of the biomaterials were studied and correlated with the biofilm data. The surface of nanoHA sintered at 830 o C (nanoHA830) showed to be more resistant to S. epidermidis attachment and accumulation than that of nanoHA sintered at 1000 o C (nanoHA1000). The biofilm formed on nanoHA830 presented differences in terms of structure, surface coverage and EPS production when compared to the one formed on nanoHA1000 surface. It was observed that topography and surface area of nanoHA surfaces had influence on the bacterial attachment and accumulation. Ci influenced bacteria attachment and accumulation on nanoHA surfaces over time. The choice of the initial inoculum concentration was relevant proving to have an effect on the extent of adherence thus being a critical point for human health if these materials are used in implantable devices. This study showed that the initial inoculum concentration and surface material properties determine the rate of microbial attachment to substrata and consequently are related to biofilm-associated infections in biomaterials.

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Influence of inoculum size of Staphylococcus aureus and Pseudomonas aeruginosa on in vitro activities and in vivo efficacy of fluoroquinolones and carbapenems

Abstract: Our results suggest that decreased bactericidal activity, or the in vitro PAE of carbapenems and fluoroquinolones, is related to the reduced in vivo protective effect against infection caused by high inoculum with S. aureus or P. aeruginosa.

Cited by 70 publications

References 20 publications

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

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

Low or High Doses of Cefquinome Targeting Low or High Bacterial Inocula Cure Klebsiella pneumoniae Lung Infections but Differentially Impact the Levels of Antibiotic Resistance in Fecal Flora

Influence of nanohydroxyapatite surface properties on Staphylococcus epidermidis biofilm formation

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