Tigecycline: A Novel Broad-Spectrum Antimicrobial

Pan-drug-resistant (PDR)Acinetobacter baumannii is an important nosocomial pathogen that poses therapeutic challenges. Tigecycline alone or in combination with agents such as colestimethate, imipenem, and/or amikacin is being used clinically to treat PDR A. baumannii infections. The purpose of this study was to compare in vitro susceptibility testing by epsilometric (Etest) methods and the checkerboard (CB) method with testing by time-kill analysis. PDR A. baumannii clinical strains representing eight unique pulsed-field gel electrophoresis clones selected from a total of 32 isolates were tested in vitro with tigecycline, colestimethate, imipenem, and amikacin in single-and two-drug combinations by using two different methods of Etest (with a fixed ratio method [method 1] and with the incorporation of the active drug in medium [method 2]) and by using CB. The three-drug combination of imipenem, tigecycline, and amikacin was also tested by CB. These results were compared to time-kill results. Synergy was consistently detected with the imipenem plus colestimethate and tigecycline plus imipenem combinations. The Etest method with active drug incorporated into the agar allowed us to detect synergy even in the presence of the active drug and was more comparable to CB and time-kill tests. Synergy was detected with the three-drug combination of imipenem, tigecycline, and amikacin by both CB and time-kill methods among several tested clones. These findings indicate the utility of synergy testing to predict activity of specific antibiotic combinations against PDR A. baumannii.In recent years Acinetobacter baumannii, an aerobic, Gramnegative coccobacillus, has emerged as an important nosocomial pathogen due to multiple drug resistance mechanisms, and it can be an extremely difficult microorganism for the clinician to treat (3,8,20,22). It causes a variety of infections that include pneumonia, wound, urinary tract, bloodstream, and intra-abdominal infections (3,8). We had experienced an increased number of cases of A. baumannii with resistant or intermediate susceptibility patterns to carbapenems over a 2-year time frame at our medical center. Growing numbers of isolates locally, nationally, and internationally have shown resistance to antibiotics such as the carbapenems, which previously had excellent activity in vitro and clinically. Our annual medical center antibiograms and a review of the literature (1,9,10,12,20,22,23,25,26) support this. Nontraditional agents, such as colestimethate (polymyxin E) and polymyxin B, despite the associated high toxicities, are being used to treat patients infected with pan-drug-resistant (PDR) A. baumannii (with pan-drug resistance defined as resistance to all routinely tested antimicrobials including carbapenems). Antibiotic resistance has also developed among some strains during treatment with these agents (10,20). Drug treatment with newer antimicrobials or antimicrobial combinations has become increasingly important to eradicate these infections.Tigecycline was approved by the Food ...

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“…This glycylcycline antimicrobial has shown a broad spectrum of activity both in vitro and in vivo, and its spectrum includes A. baumannii (21).…”

mentioning

confidence: 99%

Synergy Testing by Etest, Microdilution Checkerboard, and Time-Kill Methods for Pan-Drug-Resistant Acinetobacter baumannii

Sopirala

Mangino

Gebreyes³

et al. 2010

Antimicrob Agents Chemother

256

227

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“…Tigecycline is the first glycylcycline approved for clinical use (16). It can be oxidized when added to a broth medium that has been oxygenated during storage (13) or when tigecycline-containing broth is stored before inoculation.…”

mentioning

confidence: 99%

High Concentrations of Manganese in Mueller-Hinton Agar Increase MICs of Tigecycline Determined by Etest

et al. 2009

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MICs of tigecycline determined by Etest were 4 to 12 times (three ATCC strains) and 2 to 8 times (50 clinical isolates) higher in Mueller-Hinton agar from Merck than in Mueller-Hinton agar from either Oxoid or Difco. This was related to a much higher concentration of manganese in the medium from Merck.Tigecycline is the first glycylcycline approved for clinical use (16). It can be oxidized when added to a broth medium that has been oxygenated during storage (13) or when tigecycline-containing broth is stored before inoculation. This can be solved using freshly autoclaved broth or recently prepared solid media (2) and is expected to be avoided in the disk diffusion or gradient diffusion (Etest) assays.During a nation-wide study in Spain on the activity of tigecycline against clinical isolates using Etest strips (AB Biodisk, Solna, Sweden), the results in our center were up to 16 to 20 times higher than those obtained in other centers (A. Pérez, Wyeth Farma S.A., Spain, personal communication). After excluding the possibility that some technical error occurred in our laboratory, we hypothesized that these results could be related to differences in the composition of the Mueller-Hinton agar used in different laboratories, as the commercial source for this medium in our center (Merck) was different from that in many other laboratories in Spain.In this study, the activity of tigecycline determined with Etest strips on two different lots of commercially available MuellerHinton agar from Oxoid (Basingstoke, Hampshire, England; lots 418599 and 456733), Difco (Difco Mueller-Hinton agar [BD, Sparks, MD]; lots 6093187 and 6177851), and Merck (Darmstadt, Germany; lots VL379337507 and VL546637607) was evaluated. We also determined the effect that differences in the concentrations of ions of the evaluated Mueller-Hinton agars may have on the in vitro activity of tigecycline.In a preliminary study, five clinical isolates (selected among those we already tested in the multicenter study in Spain) and four reference strains, namely, Escherichia coli ATTC 25922, Pseudomonas aeruginosa ATCC 27953, Staphylococcus aureus 29213, and Enterococcus faecalis 29212, were evaluated. MICs of tigecycline for these two groups of organisms were consistently 4 to 12 times higher in the medium from Merck than in the medium from Difco or Oxoid, except for the P. aeruginosa ATCC strain (MICs of 64 to 128 g/ml in the three media) (data not shown).In a second phase, MICs of tigecycline for 50 clinical isolates (one per patient; clonally unrelated as assessed by repetitive extragenic palindromic PCR and/or pulsed-field gel electrophoresis) were determined in duplicate experiments on different days. Extended-spectrum ␤-lactamase (ESBL) production was confirmed by disk diffusion (4). Resistance to methicillin in S. aureus and to vancomycin in Enterococcus faecium was confirmed by PCR detection of the mecA (9) and vanA (12) genes, respectively. MICs of tigecycline were also determined by microdilution, according to CLSI guidelines (5) using fresh Mueller...

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“…Tigecycline is the first member of the glycylcyclines. It is structurally similar to tetracyclines and acts as a protein synthesis inhibitor by binding to the 30S ribosomal subunit of bacteria [121] and [122]. Its bacteriostatic activity is maintained in the presence of several resistance mechanisms that affect other antibiotics and it covers a variety of Gram-positive and Gramnegative bacteria (including MRSA, S. maltophilia, A. baumannii and multidrug-resistant Enterobacteriaceae), anaerobes and atypical bacteria.…”

Section: Telithromycinmentioning

confidence: 99%

“…It may also cause photosensitivity, pseudotumour cerebri and pancreatitis [121], [122] and [123]. Its use is to be avoided in young children and during pregnancy owing to its effects on teeth and bone.…”

Section: Telithromycinmentioning

confidence: 99%

New antibiotics for paediatric use: A review of a decade of regulatory trials submitted to the European Medicines Agency from 2000—Why aren’t we doing better?

Garazzino¹,

Lutsar²,

Bertaina³

et al. 2013

International Journal of Antimicrobial Agents

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New initiatives have been introduced in Europe and the USA to encourage more rapid development of antibiotics. The need to ensure these new antibiotics can be safely used in children, and especially neonates, is important owing to high antimicrobial resistance in these patient groups. This review aims to determine what lessons can be learnt from the recent regulatory processes to speed up access to new medicines for children, focusing on antibiotics licensed for adults by the EMA since 2000. For the 11 newly approved antibiotics, 31 clinical trials enrolling children in Europe were identified. However, many of these trials included both adults and children but did not provide a subset analysis for paediatrics, limiting the relevance of their findings. Some studies have been prematurely terminated and others are apparently active but are still not yet recruiting patients. Among paediatric-specific studies, 18 evaluate safety and efficacy of new compounds, 4 are pharmacokinetic studies, but only 2 focus on neonates. Nearly all studies with an agreed Paediatric Investigation Plan have just started or are not yet recruiting. For most antibiotics, despite adult phase 3 studies being completed, with specific concerns for particular drugs already noted, it will take another 3-5 years before adequate prescribing information becomes available for paediatricians. Evidence from this review suggests that we could do better. Lessons should be learnt from paediatric antiretroviral development, with neonatal and paediatric pharmacokinetic, clinical trial and pharmacovigilance drug development programmes being run directly in parallel with adult studies-not a decade behind.

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Tigecycline: A Novel Broad-Spectrum Antimicrobial

Cited by 65 publications

References 33 publications

Synergy Testing by Etest, Microdilution Checkerboard, and Time-Kill Methods for Pan-Drug-Resistant Acinetobacter baumannii

Synergy Testing by Etest, Microdilution Checkerboard, and Time-Kill Methods for Pan-Drug-Resistant Acinetobacter baumannii

High Concentrations of Manganese in Mueller-Hinton Agar Increase MICs of Tigecycline Determined by Etest

New antibiotics for paediatric use: A review of a decade of regulatory trials submitted to the European Medicines Agency from 2000—Why aren’t we doing better?

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