Comparative in vitro activities of tigecycline (GAR-936) and other antimicrobial agents against Stenotrophomonas maltophilia

Carmen Betriu*, Iciar Rodríguez-Avial, Blas Ali Sánchez, María Gómez and Juan J. Picazo

Department of Clinical Microbiology, Hospital Clínico San Carlos, Plaza Cristo Rey s/n, 28040 Madrid, Spain

Keywords: tigecycline activity, Stenotrophomonas maltophila

Sir,

Stenotrophomonas maltophilia is a ubiquitous, non-fermentative, Gram-negative bacillus that has emerged as an increasingly important nosocomial pathogen, especially in immunocompromised patients. S. maltophilia is usually hospital acquired and has been associated with a wide spectrum of human diseases such as respiratory tract infections, bacteraemia, post-operative wound infections, and urinary and other serious infections including pneumonia, endocarditis, septicaemia and meningitis. Risk factors for the development of S. maltophilia infection include previous exposure to broad-spectrum antibiotics, prolonged hospitalization, malignancy, neutropenia and the use of intravascular devices.1

As S. maltophilia is inherently resistant to several antimicrobial agents, few therapeutic options remain for the treatment of infections caused by this organism. Resistance to ß-lactam agents is mediated by the elaboration of several inducible metallo-ß-lactamases and cephalosporinases and decreased outer membrane permeability.1 S. maltophilia isolates rapidly develop resistance to aminoglycosides and quinolones by mutation in the genes encoding outer membrane proteins. Efflux mechanisms have been recognized as contributing to the intrinsic and acquired multidrug resistance of S. maltophilia.2

Tigecycline (formerly GAR-936) (Wyeth Pharmaceuticals, Philadelphia, PA, USA), a glycylcycline, is a new semisynthetic derivative of minocycline, chemically characterized as a 9-t-butylglycylamido-minocycline, with a broad spectrum of activity against aerobic and anaerobic bacteria.3 Tigecycline, which acts by inhibiting protein synthesis, shows activity against bacterial isolates containing the major tetracycline resistance mechanisms (ribosomal protection and active efflux) and retains activity against minocycline-susceptible microorganisms.3 Intravenous tigecycline was found to be significantly more efficacious than minocycline against infections caused by Staphylococcus aureus and Escherichia coli strains harbouring characterized tetracycline resistance determinants.3

The aim of this study was to evaluate the in vitro activity of tigecycline in comparison with that of tetracycline and minocycline and other antimicrobials (listed in Table 1) with activity against S. maltophilia.


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Table 1. Comparative activity of tigecycline and other antimicrobial agents against Stenotrophomonas maltophilia isolates
 
We studied a total of 195 clinical isolates of S. maltophilia collected in the Department of Clinical Microbiology of Hospital Clínico San Carlos from 1997 to 2000. Each organism was identified using the ID 32 GN system (bioMérieux, Marcy l’Étoile, France). The clinical sources of the isolates were as follows: skin and soft tissue (110), respiratory tract (35), urine (27), blood (11), catheter (seven) and others (five). Only one isolate per patient was studied to avoid duplication, and outbreak strains were excluded. Reference strains Pseudomonas aeruginosa ATCC 27853 and E. coli ATCC 35218 were used as controls. Antimicrobial susceptibility tests were performed by the NCCLS reference agar dilution method.4 MICs were interpreted according to NCCLS criteria for non-Enterobacteriaceae.5

As recently reported by Tripodi et al.,6 the majority of our isolates were from wounds and other skin lesions, whereas in most published studies the respiratory tract has been the main clinical source. Results of susceptibility tests are shown in Table 1. The MICs of tigecycline were two dilutions higher than those of minocycline and three to four dilutions lower than those of tetracycline. The new glycylcycline inhibited 94.4% of the isolates tested at 4 mg/L. When comparing MIC50 and MIC90 values, tigecycline displayed greater activity than amikacin, ceftazidime and ticarcillin–clavulanate. Organisms resistant to these antibiotics showed tigecycline MICs of 0.25–4 mg/L. In this study, the MIC50, MIC90 and MIC range for tigecycline were similar to those previously reported by Petersen et al.3 The majority (90.2%) of isolates were resistant to tetracycline. By comparison, 43.1% of isolates were resistant to ceftazidime and 56.4% to amikacin.

More than 85% of our isolates were susceptible to ticarcillin–clavulanate and 12.8% were intermediately susceptible. Although in most studies ticarcillin–clavulanate remains the most effective agent among the ß-lactams tested, Barbier-Frebourg et al.7 observed a dramatic increase in the prevalence of ticarcillin–clavulanate resistance among S. maltophilia isolates in Rouen, France.

The antimicrobial of choice in S. maltophilia infections is trimethoprim–sulfamethoxazole, and according to most studies this antibiotic is still the most effective agent tested. In our study, 98% of the isolates were susceptible to trimethoprim–sulfamethoxazole. A considerable variation among rates of susceptibility to this antibiotic has been reported during the last 2 years, ranging from 91%7 to 26%.6 Methodological problems associated with susceptibility testing of S. maltophilia could be in part responsible for the differences observed among susceptibility profiles of S. maltophilia isolates. At present there are no standardized methods of susceptibility testing or specific interpretative criteria for this microorganism. Because trimethoprim–sulfamethoxazole exhibits only bacteriostatic activity against most isolates, it has been proposed that patients should receive a combination of trimethoprim–sulfamethoxazole and either ticarcillin–clavulanate or an extended-spectrum cephalosporin such as ceftazidime.8

The high in vitro activity of tigecycline against S. maltophilia isolates confirmed in this study indicates that this new glycylcycline could be considered as an additional agent in the treatment of infections caused by this organism. Clinical studies evaluating the efficacy of this new agent are warranted.

Acknowledgements

This study was presented at the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 16–19 December 2001.

Footnotes

* *Corresponding author. Tel: +34-913303486; Fax: +34-913303478; E-mail: cbetriu{at}efd.net Back

References

1 . Denton, M. & Kerr, K. G. (1998). Microbiological and clinical aspects of infections associated with Stenotrophomonas maltophilia. Clinical Microbiology Reviews 11, 57–80.[Abstract/Free Full Text]

2 . Zhang, L., Li, X.-Z. & Poole, K. (2000). Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a multidrug efflux system. Antimicrobial Agents and Chemotherapy 44, 287–93.[Abstract/Free Full Text]

3 . Petersen, P. J., Jacobus, N. V., Weiss, W. J., Sum P. E. & Testa, R. T. (1999). In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrobial Agents and Chemotherapy 43, 738–44.[Abstract/Free Full Text]

4 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA, USA.

5 . National Committee for Clinical Laboratory Standards. (2001). Performance Standards for Antimicrobial Susceptibility Testing: Eleventh Informational Supplement M100-S11. NCCLS, Wayne, PA, USA.

6 . Tripodi, M. F., Andreana, A., Sarnataro, G., Ragone, E., Adinolfi, L. E. & Utili, R. (2001). Comparative activities of isepamicin, amikacin, cefepime, and ciprofloxacin alone or in combination with other antibiotics against Stenotrophomonas maltophilia. European Journal of Clinical Microbiology and Infectious Diseases 20, 73–5.[ISI][Medline]

7 . Barbier-Frebourg, N., Boutiba-Boubake, I., Nouvello, M. & Lemelan, J. (2000). Molecular investigation of Stenotrophomonas maltophilia isolates exhibiting rapid emergence of ticarcillin–clavulanate resistance. Journal of Hospital Infection 45, 35–41.[ISI][Medline]

8 . Muder, R. R., Harris, A. P., Muller, S., Edmond, M., Chow, J. W., Papadakis, K. et al. (1996). Bacteremia due to Stenotrophomonas (Xanthomonas) maltophilia: a prospective multicenter study of 91 episodes. Clinical Infectious Diseases 22, 508–12.[ISI][Medline]