Pharmacokinetics and pharmacodynamics of oral cephalosporins as critical factors in choice of antibiotics

Novelli, Andréa; Fallani, Stefania; Cassetta, Maria Iris; Conti, Silvia

doi:10.1016/s0924-8579(00)00285-5

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…In vitro susceptibility studies. MIC values were determined by a broth microdilution assay according to Clinical and Laboratory Standards Institute (CLSI) reference methods (8). Determinations were performed in duplicate on three separate occasions.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Activity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

Liang

Wang

et al. 2014

Antimicrob Agents Chemother

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Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such as Escherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT >MIC ) was the PK-PD index that best correlated with efficacy (R 2 ‫؍‬ 73% for E. coli, compared with 13% for the maximum concentration of the free drug in serum [fC max ]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [fAUC 0-24 ]/ MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total cefquinome doses administered every 4 h to treat animals infected with four additional E. coli isolates. A sigmoid maximum-effect (E max ) model was used to estimate the magnitudes of the %fT >MIC associated with net bacterial stasis, a 1-log 10 CFU reduction from baseline, and a 2-log 10 CFU reduction from baseline; the corresponding values were 28.01% ؎ 2.27%, 37.23% ؎ 4.05%, and 51.69% ؎ 9.72%. The potent bactericidal activity makes cefquinome an attractive option for the treatment of infections caused by E. coli.

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Section: Methodsmentioning

confidence: 99%

In Vivo Activity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

Liang

Wang

et al. 2014

Antimicrob Agents Chemother

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“…Previous studies with ␤-lactams have established that the percentage of a 24-h dosing interval in which the free-drug concentration exceeds the MIC (%T ϾfMIC ) is the pharmacokineticpharmacodynamic (PK-PD) parameter best linked with efficacy (10)(11)(12)(13)(14)(15)(16). The goal of our studies was to characterize the PK-PD parameter that is predictive of the efficacy of cefquinome against susceptible and resistant S. aureus strains in a neutropenic murine infection model.…”

mentioning

confidence: 99%

Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection

Wang

Ding

et al. 2014

Antimicrob Agents Chemother

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bCefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against Staphylococcus aureus. The objective of our study was to examine the in vivo activity of cefquinome against S. aureus strains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo postantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected with S. aureus strain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and produced in vivo PAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T >MIC ) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additional S. aureus isolates. A sigmoid maximum effect (E max ) model was used to estimate the magnitudes of the ratios of the %T that the free-drug serum concentration exceeded the MIC (%T >fMIC ) associated with net bacterial stasis, a 0.5-log 10 CFU reduction from baseline, and a 1-log 10 CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused by S. aureus. Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is an important human pathogen that is also an emerging concern in veterinary medicine and animal agriculture. All known mammalian species, including common laboratory rodent and rabbit species, are susceptible to colonization with S. aureus. MRSA has been shown to have a prevalence of 39% and 24.9% in pigs in the Netherlands (1) and Canada (2), respectively, and 28% in veal calves in the Netherlands (3). A Canadian study identified MRSA in 6.3% of ground pork and 5.6% of ground beef but in 32% and 45% of positive pork and beef samples, respectively (4). Some samples of commercially sold meat products in Japan were also found to harbor MRSA strains (5). Because of its ability to colonize a wide range of species, S. aureus can be readily transmitted from one species to another, including from humans to animals and vice versa. Moreover, a majority of S. aureus isolates are resistant to various antimicrobial agents (6), and thus, there are limited antimicrobial options for treatment; accordingly, there is a growing need for more potent antimicrobials to attack these resistant pathogens. Cefquinome (formerly HR 111V) is a fourth-generation cephalosporin developed solely for veterinary use. It displays antimicrobial activities in vitro and in vivo agains...

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“…For time-dependent antibiotics like β-lactams, the parameter that better defines bactericidal efficacy and that allows controlling the emergence of resistant strains is T > MIC. 28 This is the time the serum concentration of the agent maintains above the minimum inhibitory concentration (MIC) for a given pathogen, expressed as percentage of dose interval. 29 On the contrary, in case of concentration-dependent antibiotics, such as fluoroquinolones and semi-synthetic macrolides (azithromycin and clarithromycin), the pharmacological goal is obtained by attaining adequate values of the ratio between either the area under the plasma concentration versus time curve (AUC) and the MIC (AUC/MIC), or the peak plasma concentration (Cmax) and the MIC (Cmax/ MIC).…”

Section: Topic: Pharmacologic Issues Involved In the Practice Of Presmentioning

confidence: 99%

“…This ensures that concentrations above the MIC should be adequately maintained for a sufficiently long time interval along the 24-h period. 28 The information on PK/PD features of the different classes of antibiotics offer a useful tool to the clinician for the choice of the most appropriate drug and of the most effective dose and route of administration in the therapy of LRTIs. The panel reached an almost complete agreement (97%) on the essential role of patient's disease severity in determining the initial dose and the route of administration of cephalosporins for the treatment of LRTIs.…”

Section: Topic: Clinical Considerations On the Management Of Patientsmentioning

confidence: 99%

The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach

Blasi

Concia

Prato

et al. 2017

Journal of Chemotherapy

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Lower respiratory tract infections (LRTIs) cause high morbidity and mortality worldwide. Empiric therapy often base the choice of antibiotic treatment on antibacterial spectrum of the agent rather than on its pharmacological properties or the pathogen resistance profile. Inappropriate prescribing leads to therapeutic failure and antibiotic resistance, with increasing direct and indirect health costs. A consensus on appropriate prescribing in LRTI therapy was appraised by this Delphi exercise, based on a panel of 70 pulmonologists, coordinated by a Scientific Committee of nine experts in respiratory medical care. Full or very high consensus was reached on several issues, including the role of oral cephalosporins in first-line treatments of LRTIs and the appropriateness of cefditoren, with balanced spectrum and high intrinsic activity, in LRTI treatment. Evidence-based medicine approach and a comprehensive process of disease management, from diagnosis to therapy and follow-up, should guide antibiotic prescribing.

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Pharmacokinetics and pharmacodynamics of oral cephalosporins as critical factors in choice of antibiotics

Cited by 15 publications

References 31 publications

In Vivo Activity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

In Vivo Activity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection

The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach

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