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In Vitro Antibacterial Activities of Tigecycline I
In Vitro Antibacterial Activities of Tigecycline I
In Vitro Antibacterial Activities of Tigecycline I
doi:10.1093/jac/dki477
Advance Access publication 23 January 2006
Infectious Disease Discovery Research, Wyeth Research, Pearl River, NY 10965, USA
Received 7 October 2005; returned 16 November 2005; revised 30 November 2005; accepted 12 December 2005
Objectives: This study was undertaken to determine the interaction of tigecycline with 13 select
antimicrobial agents against a wide variety of Gram-negative and Gram-positive bacterial isolates.
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The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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Petersen et al.
Materials and methods any combination with tigecycline, against any of the strains tested
(Table 1). A higher percentage of synergistic combinations with
Bacterial strains tigecycline were observed with amikacin (56%), ampicillin/sulbac-
Representative isolates of clinically relevant species, collected during tam (33%), piperacillin/tazobactam (50%) and rifampicin (33%).
clinical trials, from various medical centres in the United States Interestingly, 73% of the Proteus spp. showed synergy when tige-
and Canada between 1990 and 2000, were used in this study. The cycline was tested in combination with minocycline. No other clear
Gram-negative organisms used were chosen from the collection at trend could be established for synergy occurring with any other
random and do not represent any specific resistance mechanism. bacterial species and drug combinations.
The Gram-positive organisms were also chosen from the clinical With the Gram-positive isolates, rifampicin displayed a
collection; however, these were chosen to represent important synergistic effect with tigecycline for 66% of the isolates tested
resistance mechanisms (MRSA, PRSP and VRE). (Table 2). The majority of these strains showing synergy were
Enterococcus spp. including vancomycin-resistant (VRE) strains
Antimicrobial agents and penicillin-resistant Streptococcus pneumoniae (PRSP). Con-
This study was designed to evaluate tigecycline in combination with versely, the combination of vancomycin and tigecycline resulted
a wide variety of antimicrobial agents in support of the use of in a larger percentage of no interaction (71%) than synergistic
tigecycline in combination therapy for a compassionate use clinical effects (29%) against the Gram-positive isolates. Antagonism
protocol. The antimicrobial agents used in the study were: tigecycline, was not observed in this analysis.
piperacillin, tazobactam (Wyeth Research, Pearl River, NY, USA), In order to confirm a result of synergy (FICI 0.5) by the
ampicillin, minocycline, amikacin, ciprofloxacin, vancomycin, chequerboard MIC method, time-kill kinetic studies were per-
rifampicin, polymyxin B, colistin (Sigma-Aldrich Co., St Louis, formed with tigecycline combinations against selected bacterial
MO, USA), azithromycin, sulbactam, imipenem (USP, Rockville, species.9 The antibiotics were tested at concentrations based
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Tigecycline synergy
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Petersen et al.
a screening test.38 The chequerboard MIC test suffers due to 2. Petersen PJ, Bradford PA, Weiss WJ et al. In vitro and in vivo
lack of reproducibility and only measures bacteriostatic effects.5 activities of tigecycline (GAR-936), daptomycin, and comparative
Variability in the test as well as testing a bacteriostatic agent in antimicrobial agents against glycopeptide-intermediate Staphylococcus
combination with mostly bactericidal agents may be the cause for aureus and other resistant Gram-positive pathogens. Antimicrob Agents
Chemother 2002; 46: 2595601.
the overestimate of synergy experienced with the chequerboard
test. Accordingly, synergy testing performed by time-kill 3. Rybak MJ McGrath BJ. Combination antimicrobial therapy
for bacterial infections. Guidelines for the clinician. Drugs 1996; 52:
kinetics was used to confirm the results of chequerboard MIC
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testing, as is standard protocol in many laboratories.7,8
The drug concentrations used in the time-kill kinetic studies, 4. White R, Burgess D, Manduru M et al. Comparison of three different
in vitro methods of detecting synergy: time-kill, checkerboard, and E test.
based on the MIC determined in the FICI analysis, were expected
Antimicrob Agents Chemother 1996; 40: 191418.
to have an effect in the growth assay. The fact that these concen-
5. Rand KH, Houck HJ, Brown P et al. Reproducibility of the micro-
trations do not result in synergy in the more constrained experi-
dilution checkerboard method for antibiotic synergy. Antimicrob Agents
mental format suggests again that the chequerboard analysis is
Chemother 1993; 37: 613615.
overestimating synergy, possibly due to the reproducibility issue
6. Alou L, Cafini F, Sevillano D et al. In vitro activity of mupirocin and
inherent in the test.5
amoxicillin-clavulanate alone and in combination against staphylococci
Although synergy detected by in vitro chequerboard studies including those resistant to methicillin. Int J Antimicrob Agents 2004;
could not in the majority of cases be confirmed by time-kill kinetic 23: 5136.
analysis, the lack of antagonism seen with tigecycline com-
7. Jacqueline C, Navas D, Batard E et al. In vitro and in vivo
binations in both studies is an encouraging outcome suggesting synergistic activities of linezolid combined with subinhibitory concentra-
that tigecycline may prove to be effective in combination therapy tions of imipenem against methicillin-resistant Staphylococcus aureus.
as well as in monotherapy. Antimicrob Agents Chemother 2005; 49: 4551.
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