Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

Meagher, Alison; Passarell, Julie; Cirincione, Brenda; Wart, Scott A. Van; Liolios, Kathryn; Babinchak, Timothy; Ellis-Grosse, Evelyn J.; Ambrose, Paul G.

doi:10.1128/aac.01084-06

Cited by 106 publications

(79 citation statements)

References 22 publications

(24 reference statements)

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“…The dosing regimen that would produce a drug exposure in vivo that is similar to that in humans, quantified by the area under the concentration-time curve from 0 to 24 h (AUC0-24 ) in blood, was replicated (3,4). As such, a free (unbound) TGC AUC 0-24 of 1.13 (or a total-bound and unbound-TGC AUC 0-24 of 5.39 with 79% protein binding), observed in humans following the regimen of a 100-mg loading dose with subsequent 50-mg doses q12h (4,5), was simulated over each of the three 24-h intervals in the mice. The in vivo regimen utilized in this current study was 12.5 mg/kg q24h, administered via subcutaneous (s.c.) injection, which was previously determined to produce a drug exposure similar to that in humans (2,6).…”

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confidence: 98%

Tigecycline Displays In Vivo Bactericidal Activity against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae after 72-Hour Exposure Period

Tessier

Nicolau

2013

Antimicrob Agents Chemother

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Progressively enhanced activity of a humanized tigecycline (TGC) regimen was noted over 3 days against an extended-spectrum-␤-lactamase (ESBL)-producing Escherichia coli isolate and an ESBL-producing Klebsiella pneumoniae isolate. Bacterial density reduction approximated 3 log 10 approaching bactericidal activity at 72 h. This level of activity has not been previously noted for compounds such as tetracyclines, normally considered bacteriostatic antimicrobials. Extended regimen studies in vivo may aid in better delineation of antimicrobial effects, producing improved correlation with clinical outcomes. Historically, in vitro and in vivo pharmacodynamic (PD) assessments have been conducted over 24 h. While these studies have been noted to correlate with clinical outcomes for rapidly bactericidal agents (i.e., fluoroquinolones or aminoglycosides), these PD endpoints appear more poorly correlated for agents such as the tetracyclines and related derivatives which have slower killing profiles in vitro. The tetracyclines and the class-related extended-spectrum agents, such as tigecycline (TGC), have demonstrated bacteriostatic activity in in vitro studies against a variety of bacterial strains (1). In a recent study using the endpoint of reduction in numbers of CFU after 24 h of TGC exposure against several Escherichia coli and Klebsiella pneumoniae isolates, we noted antibacterial activity in both immunocompromised and immunocompetent mice (2). The majority of doses were bacteriostatic at best. The maximum reduction in numbers of CFU was 2 log 10 over this 24-h exposure period; however, these effects were noted only when exposures were well above that typically seen in humans. In addition, it was also noted that the in vivo exposures required to produce substantial reductions in numbers of CFU in the immunocompromised murine model were well in excess of that recognized to produce good clinical and microbiologic outcomes in patients (2). While the immunocompromised model appeared to have exposures discordant to that observed in humans, the immunocompetent model required exposures similar to that observed in patients. Therefore, in the current study, we sought to determine the magnitude of bacterial kill over an extended treatment period of 72 h using an exposure in immunocompetent animals that would mimic the regimen of a 100-mg loading dose with subsequent 50-mg doses every 12 h (q12h) of TGC in humans.Two extended-spectrum-␤-lactamase (ESBL)-producing clinical strains, one E. coli (E. coli strain 363; TGC MIC, 0.125 g/ml) and one K. pneumoniae (K. pneumoniae strain 404; TGC MIC, 0.25 g/ml), provided by Tetraphase Pharmaceuticals, Inc. IN). These studies were approved by and followed the guidelines of the Institutional Animal Care and Use Committee at our facility. Bacterial colonies of a fresh subculture of each isolate were suspended in sterile 0.9% sodium chloride to produce a suspension of approximately 10 8 CFU/ml. Final inoculum concentrations were confirmed by plating serial dilutions of inocula on Trypticase ...

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confidence: 98%

Tigecycline Displays In Vivo Bactericidal Activity against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae after 72-Hour Exposure Period

Tessier

Nicolau

2013

Antimicrob Agents Chemother

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“…During the course of its development, tigecycline has been the subject of several pharmacokinetic-pharmacodynamic (PK-PD) analyses, using data from animal infection models as well as data from clinical trials of patients suffering from complicated skin and skin structure infections or those with complicated intra-abdominal infections (3,4,8). These analyses have characterized the magnitude of the ratio of the area under the concentration-time curve at 24 h to the MIC of the pathogen (AUC 0-24 :MIC), the PK-PD measure most predictive of outcome, which is associated with efficacy.…”

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confidence: 99%

Pharmacokinetics-Pharmacodynamics of Tigecycline in Patients with Community-Acquired Pneumonia

Rubino

Bhavnani

Forrest

et al. 2012

Antimicrob Agents Chemother

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Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from communityacquired pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time curve at 24 h to the MIC of the pathogen (fAUC 0-24 :MIC) of >12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time to fever resolution (P ‫؍‬ 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87 mg · hr/liter (P ‫؍‬ 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting (P ‫؍‬ 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from baseline in total bilirubin is unlikely to be clinically significant.

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“…9 Tigecycline also needs higher area under curve (AUC)/MIC ratios for efficacy, possibly due to extracellular fluid leak in septic patients with HAP or VAP. 10 This change in lung exposure, in the presence of similar serum exposure, could explain a reduced response with Tigecycline.…”

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confidence: 99%

A retrospective observational study of the impact of Tigecycline in treating multidrug resistant pneumonia

Paul

2017

Int J Clin Trials

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Background: Few antimicrobials are currently active to treat extensively drug resistant (XDR) gram-negative bacilli infections. This represents a serious global public health concern. Critically ill patients face the brunt of majority of these infections. Tigecycline has coverage for a majority of these XDR infections (with the exception of Pseudomonas aeruginosa), but is not currently approved for hospital-acquired pneumonia. Nevertheless it is being commonly used for this indication though many meta-analysis have suggested an increased risk of death in patients receiving this antibiotic. Methods: In this retrospective analysis we compared the mortality rates between a Tigecycline based and a non Tigecycline based therapy for XDR infections in the critically ill over a period of 12 months. A total of 93 patients were included in the study.Results: Tigecycline group had significantly increased risk for in hospital mortality with an odds ratio of 6.0 and 95% CI of 1.37 to 26.12 with a p value of 0.01. But such a difference was not evident in 14 day mortality. Conclusions: Initiation of Tigecycline for multidrug resistant, pneumonia needs to be re-thought. Only a small percentage of patients with pneumonia with in-vitro sensitivity having low minimum inhibitory concentration (MIC) would benefit from the drug. Even in this group the risk of increased mortality needs to be carefully considered before Initiation of therapy.

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Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

Cited by 106 publications

References 22 publications

Tigecycline Displays In Vivo Bactericidal Activity against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae after 72-Hour Exposure Period

Tigecycline Displays In Vivo Bactericidal Activity against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae after 72-Hour Exposure Period

Pharmacokinetics-Pharmacodynamics of Tigecycline in Patients with Community-Acquired Pneumonia

A retrospective observational study of the impact of Tigecycline in treating multidrug resistant pneumonia

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