A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae

Vasilev, K.; Reshedko, G. K.; Orăsan, Remus Ioan; Sánchez, Miguel; Teras, J; Babinchak, Timothy; Dukart, Gary; Cooper, Angel; Dartois, Nathalie; Gandjini, Hassan; Orrico, R.; Ellis-Grosse, Evelyn J.

doi:10.1093/jac/dkn249

Cited by 95 publications

(56 citation statements)

References 43 publications

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“…Similar results have been observed in other tigecycline in vitro and surveillance studies showing that activity does not appear to be affected by porin loss, ESBL, AmpC, or carbapenemase production or a combination thereof (2,4,9). In this context, Vasilev et al (23) assessed the in vitro and clinical data of multidrug-resistant enterobacteria and evaluated the effectiveness of tigecycline in relation to the microbiological and clinical outcomes in these organisms. In the noncomparative study (23), the microbiological eradication and clinical cure rates at test of cure in the microbiologically evaluable population were 6 of 6 and 5 of 6 in patients infected with K. pneumoniae and 4 of 6 and 4 of 9 in patients infected with E. coli, respectively.…”

Section: Discussionsupporting

confidence: 72%

“…In this context, Vasilev et al (23) assessed the in vitro and clinical data of multidrug-resistant enterobacteria and evaluated the effectiveness of tigecycline in relation to the microbiological and clinical outcomes in these organisms. In the noncomparative study (23), the microbiological eradication and clinical cure rates at test of cure in the microbiologically evaluable population were 6 of 6 and 5 of 6 in patients infected with K. pneumoniae and 4 of 6 and 4 of 9 in patients infected with E. coli, respectively. In the study, it is important to note that three cIAI patients infected with E. coli were removed from the microbiologically evaluable population when it was discovered that the initial surgical intervention for cIAI was inadequate.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, tigecycline is FDA approved for complicated intraabdominal infections (cIAI) and complicated skin-skin structure infections (15). With high susceptibilities demonstrated in surveillance studies (2) and positive clinical outcomes shown in trial data from subpopulations infected with ESBL-producing Enterobacteriaceae (6,23), tigecycline has been increasingly utilized as a treatment option. Given these occurrences and the few available studies describing the exposure-response relationship for the treatment of gram-negative organisms (15,19,21), it seems reasonable to uncover the pharmacodynamics of tigecycline.…”

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confidence: 99%

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In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates

Nicasio¹,

Crandon²,

Nicolau

2009

Antimicrob Agents Chemother

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Tigecycline is a glycylcycline with activity against Enterobacteriaceae, including multidrug-resistant isolates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamase (ESBL) and carbapenemases. Herein, we used an in vivo murine thigh model to characterize the pharmacodynamic profile of tigecycline against genotypically and phenotypically diverse K. pneumoniae and E. coli isolates. Doses of 3.125 to 300 mg/kg, divided 1 to 6 times daily, were administered subcutaneously against six (two nonresistant, one carbapenemase, and three ESBL producing) K. pneumoniae strains and five (two nonresistant and three ESBL producing) E. coli strains. The phenotypic profile (reported tigecycline MIC) for all isolates ranged from 0.125 to 2 g/ml. Mean correlation coefficients of free (f) drug exposures (percentage of the dosing interval that free drug concentration remained above the MIC [fT>MIC], the ratio of the free drug area under the concentration-time curve/MIC [fAUC/MIC], and the ratio of maximum concentration of free drug in serum/MIC) for all 11 isolates were 0.595, 0.969, and 0.897, respectively. The fAUC/MIC was the pharmacodynamic parameter that best described the efficacy of tigecycline against both E. coli and K. pneumoniae. Interestingly, reductions in the number of CFU were noted even though doses achieved an fT>MIC of 0%. With respect to fAUC/MIC in the neutropenic model, the cumulative 80% and 50% effective pharmacodynamic indexes (EI 80 and EI 50 ) for all 11 isolates were 8.4 and 4.7, respectively. An experiment in nonneutropenic mice infected with an ESBL-producing E. coli and K. pneumoniae isolate resulted in the lowest tigecycline fAUC/MIC EI 80 and EI 50 values at 1.8 and 1.0 for E. coli and 1.7 and 1.6 for K. pneumoniae. While the phenotypic profile of tigecycline appeared to drive efficacy irrespective of ESBL or carbapenemase production, the presence of a competent immune system markedly reduced this required exposure.With the recent worldwide emergence of carbapenemaseproducing Klebsiella pneumoniae and the steadily increasing prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (11,17,24), the need for more antibiotics in the rapidly deteriorating armamentarium becomes even more important (18).Tigecycline, a glycylcycline derived from minocycline, is a novel agent displaying activity against ESBL and carbapenemase-producing K. pneumoniae and Escherichia coli (2, 4, 9). Currently, tigecycline is FDA approved for complicated intraabdominal infections (cIAI) and complicated skin-skin structure infections (15). With high susceptibilities demonstrated in surveillance studies (2) and positive clinical outcomes shown in trial data from subpopulations infected with ESBL-producing Enterobacteriaceae (6, 23), tigecycline has been increasingly utilized as a treatment option. Given these occurrences and the few available studies describing the exposure-response relationship for the treatment of gram-negative organisms (15,19,21), it seems reasonable t...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates

Nicasio¹,

Crandon²,

Nicolau

2009

Antimicrob Agents Chemother

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“…Clinicians have already been confronted with the reality of infections caused by A. baumannii strains that are resistant to all clinically available agents except polymyxins (polymyxin B and colistin) and tigecycline. 5,6 Together with the first report of plasmid-mediated polymyxin resistance in E. coli that could be transferred to other Gram-negative strains, 7 the reports send a very strong warning. Colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS), and requires conversion in vivo into the active form of colistin, a process that occurs slowly and incompletely in humans.…”

Section: Introductionmentioning

confidence: 99%

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

Rao

Bulitta

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. Methods:The pharmacodynamics of polymyxin B together with doripenem were evaluated in time -kill experiments over 48 h against 10 8 cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 10 9 cfu/mL of ATCC 19606.Results: In static time -kill studies, polymyxin B concentrations .4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a .7.5 log 10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (.8 log 10 ) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance.Conclusions: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.

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“…The clinical severity of infections with MDRAB isolates with intrinsic and acquired resistance has been exacerbated by the limited number of effective antibiotics. Although polymyxins and, possibly, tigecycline are considered to be the last resort of reliable treatments (6)(7)(8), the emergence of MDRAB resistance to these two types of antibiotics has been reported worldwide (9)(10)(11), which has created a pressing need to discover effective new alternative agents.…”

mentioning

confidence: 99%

In Vitro Potential of Lycosin-I as an Alternative Antimicrobial Drug for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Wang

Liu

et al. 2014

Antimicrob Agents Chemother

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bThe resistance of multidrug-resistant Acinetobacter baumannii (MDRAB) isolates to most traditional antibiotics results in huge challenges for infection therapy. We investigated the in vitro activities of both L-and D-lycosin-I against MDRAB. These two compounds displayed high antibacterial activities and rapid bactericidal effects against MDRAB. Moreover, the compounds retained their activity even at high salt (Mg 2؉ or Ca 2؉ ) concentrations. These results demonstrate the potential of lycosin-I to be developed as a new antibiotic.

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A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae

Abstract: In this non-comparative study, tigecycline appeared safe and efficacious in patients with difficult-to-treat serious infections caused by resistant Gram-negative organisms.

Cited by 95 publications

References 43 publications

In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates

In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

In Vitro Potential of Lycosin-I as an Alternative Antimicrobial Drug for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

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