Pharmacodynamic evaluation of tigecycline against Acinetobacter baumannii in a murine pneumonia model

Koomanachai, Pornpan; Kim, Aryun; Nicolau, David P.

doi:10.1093/jac/dkp056

Cited by 63 publications

(42 citation statements)

References 19 publications

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“…Tigecycline and ceftriaxone had the lowest MICs against both B. burgdorferi N40 and B31, compared to doxycycline and penicillin (Table 1). When the MBCs of B. burgdorferi were compared to peak serum levels obtained in previous mouse studies, the serum maximum concentrations of tigecycline and ceftriaxone were at least 100 times greater than the B. burgdorferi N40 tigecycline MBC and 70 times greater than the B. burgdorferi N40 ceftriaxone MBC (35,61,75). The MIC and MBC for B. burgdorferi N40 were essentially similar to those of B. burgdorferi B31 for any of the antibiotics tested.…”

Section: Resultsmentioning

confidence: 75%

“…The ceftriaxone treatment regimen served as a control group for comparison with previously published studies that demonstrated persistence of B. burgdorferi after treatment (13,27). Tigecycline doses were based on recently published tigecycline pharmacokinetic data in mice (35), which showed the 12.5-mg/kg dose to be similar to the serum drug concentrations achieved in humans.…”

Section: Methodsmentioning

confidence: 99%

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Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi

Barthold

Hodzic

Imai

et al. 2010

Antimicrob Agents Chemother

111

138

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The effectiveness of a new first-in-class antibiotic, tigecycline (glycylcycline), was evaluated during the early dissemination (1 week), early immune (3 weeks), or late persistent (4 months) phases of Borrelia burgdorferi infection in C3H mice. Mice were treated with high or low doses of tigecycline, saline (negative-effect controls), or a previously published regimen of ceftriaxone (positive-effect controls). Infection status was assessed at 3 months after treatment by culture, quantitative ospA real-time PCR, and subcutaneous transplantation of joint and heart tissue into SCID mice. Tissues from all saline-treated mice were culture and ospA PCR positive, tissues from all antibiotic-treated mice were culture negative, and some of the tissues from most of the mice treated with antibiotics were ospA PCR positive, although the DNA marker load was markedly decreased compared to that in saline-treated mice. Antibiotic treatment during the early stage of infection appeared to be more effective than treatment that began during later stages of infection. The viability of noncultivable spirochetes in antibiotic-treated mice (demonstrable by PCR) was confirmed by transplantation of tissue allografts from treated mice into SCID mice, with dissemination of spirochetal DNA to multiple recipient tissues, and by xenodiagnosis, including acquisition by ticks, transmission by ticks to SCID mice, and survival through molting into nymphs and then into adults. Furthermore, PCR-positive heart base tissue from antibiotic-treated mice revealed RNA transcription of several B. burgdorferi genes. These results extended previous studies with ceftriaxone, indicating that antibiotic treatment is unable to clear persisting spirochetes, which remain viable and infectious, but are nondividing or slowly dividing.

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Section: Resultsmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi

Barthold

Hodzic

Imai

et al. 2010

Antimicrob Agents Chemother

111

138

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“…However, antibiograms performed on these strains showed a rough correlation between virulence and degree of antibiotic resistance, a relationship that has not previously been investigated. The tendency for A. baumannii strains to exhibit a high level of antibiotic resistance is well established in the literature (1,2,6,7,18,20,22,27,28,33,39,49,59). Resistance is due both to chromosomally encoded resistance genes and to ones found on plasmids and transposons (12).…”

Section: Characterization Of Systemic a Baumannii Infection Five CLmentioning

confidence: 99%

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

et al. 2011

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Acinetobacter baumannii is a nosocomial pathogen with a high prevalence of multiple-drug-resistant strains, causing pneumonia and sepsis. The current studies further develop a systemic mouse model of this infection and characterize selected innate immune responses to the organism. Five clinical isolates, with various degrees of antibiotic resistance, were assessed for virulence in two mouse strains, and between male and female mice, using intraperitoneal infection. A nearly 1,000-fold difference in virulence was found between bacterial strains, but no significant differences between sexes or mouse strains were observed. It was found that microbes disseminated rapidly from the peritoneal cavity to the lung and spleen, where they replicated. A persistent septic state was observed. The infection progressed rapidly, with mortality between 36 and 48 h. Depletion of neutrophils with antibody to Ly-6G decreased mean time to death and increased mortality. Interleukin-17 (IL-17) promotes the response of neutrophils by inducing production of the chemokine keratinocyte-derived chemoattractant (KC/CXCL1), the mouse homolog of human IL-8. Acinetobacter infection resulted in biphasic increases in both IL-17 and KC/CXCL1. Depletion of neither IL-17 nor KC/CXCL1, using specific antibodies, resulted in a difference in bacterial burdens in organs of infected mice at 10 h postinfection. Comparison of bacterial burdens between IL-17a؊/؊ and wild-type mice confirmed that the absence of this cytokine did not sensitize mice to Acinetobacter infection. These studies definitely demonstrate the importance of neutrophils in resistance to systemic Acinetobacter infection. However, neither IL-17 nor KC/CXCL1 alone is required for effective host defense to systemic infection with this organism.

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“…Protein binding was assumed to be 86%, and the target free-drug peak concentration (fC peak ) and half-life were 1.16 g/ml and 3.2 h, respectively, resulting in a target free-drug area under the concentration curve over the 12-h dosing interval (fAUC 0 -12 ) of 4.8 g · h/ml (24). Tigecycline was simulated with higher doses of 100 mg every 12 h and 200 mg every 12 h based on data from a murine pneumonia infection model, in which it was observed that the fAUC/MIC ratio was the pharmacodynamic parameter of importance predicting tigecycline efficacy against A. baumannii, and dosing regimens of Ն200 mg daily were required to achieve a 1-to 2-log reduction in organism density (25). Tigecycline pharmacokinetics were extrapolated from a study of patients infected with community-or hospital-acquired pneumonia (26) and used to simulate steady-state fAUC 0-12 exposures of 2.3 and 4.6 g · h/ml, as previously described (27).…”

mentioning

confidence: 99%

In Vitro Pharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

Hagihara

Housman

Nicolau

et al. 2014

Antimicrob Agents Chemother

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b Carbapenem-resistant Acinetobacter baumannii is increasing in prevalence. Polymyxin B and tigecycline are among the most active antibiotics used against this pathogen in vitro. Past in vitro studies, however, neglected the importance of simulating exposures observed in humans to determine their antibacterial effects. In this study, four carbapenem-resistant A. baumannii isolates were evaluated using an in vitro pharmacodynamic model. Free-drug exposures using 1 mg/kg of body weight of polymyxin B every 12 h (q12h), 100 and 200 mg tigecycline q12h, and the combination of these regimens were simulated. The microbiological responses to these treatments were measured by the change in log 10 CFU/ml over 24 h and the area under the bacterial killing and regrowth curve (AUBC). Resistance was assessed by a population analysis profile (PAP) conducted after 24 h of treatment. Polymyxin B achieved a reduction on the order of ؊2.05 ؎ 0.68 log 10 CFU/ml against these A. baumannii isolates, while all isolates grew to control levels with tigecycline monotherapy. Combination therapy with polymyxin B plus 200 mg tigecycline q12h achieved a greater reduction in bacterial density than did therapy with polymyxin B alone (؊3.31 ؎ 0.71 versus ؊2.05 ؎ 0.68 log 10 CFU/ml, P < 0.001) but not significantly different than combination therapy with 100 mg tigecycline q12h (؊2.45 ؎ 1.00 log 10 CFU/ml, P ‫؍‬ 0.370). Likewise, combination therapy with polymyxin B plus 200 mg tigecycline q12h significantly reduced the AUBC compared to that with polymyxin B alone (62.8 ؎ 8.9 versus 79.4 ؎ 10.5 log 10 CFU/ml, P < 0.05). No changes in the PAP from baseline were observed for either antibiotic alone. In this study, combination therapy with simulated exposures of polymyxin B and tigecycline at an aggressive dose of 200 mg q12h produced synergistic or additive effects on humans against these multidrug-resistant A. baumannii strains.

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Pharmacodynamic evaluation of tigecycline against Acinetobacter baumannii in a murine pneumonia model

Abstract: Tigecycline efficacy in this murine ACB pneumonia model was well predicted by fAUC/MIC. Requisite tigecycline exposures for efficacy appear to be higher for ACB pneumonia than for other pathogens reported of non-respiratory infections.

Cited by 63 publications

References 19 publications

Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi

Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

In Vitro Pharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

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