JAC
Journal of Antimicrobial Chemotherapy (2001) 47, 113–124
Correspondence Comparison of serum bactericidal activity of ceftazidime, ciprofloxacin and meropenem against Stenotrophomonas maltophilia J Antimicrob Chemother 2001; 47: 118–120 Sebastian W. Lemmena*, Helga Häfnera, Ralf R. Reinertb, Dirk Zolldanna, Klaus Kümmererc and Rudolf Lüttickenb a
Department of Infection Control, University Hospital Aachen, Germany; bInstitute of Medical Microbiology, University Hospital, Aachen, Germany; cInstitute for Hygiene and Environmental Medicine, University Hospital, Freiburg, Germany *Correspondence address. Zentralbereich für Krankenhaushygiene, Universitätsklinikum Aachen, 52072 Aachen, Germany. Tel: 49-241-80-89843; Fax: 49-241-8888-540; E-mail:
[email protected] Sir, The emergence of Stenotrophomonas maltophilia as a cause of life-threatening disease, particularly in severely immunocompromised patients, is becoming increasingly prominent. S. maltophilia is inherently resistant to multiple antimicrobial agents. A high-dose regimen of cotrimoxazole is the treatment of choice for this infection, but cotrimoxazole resistance has been documented.1 In addition, toxicity of the sulphonamide component of the combination may limit the value of this approach, especially for patients in the intensive care unit. Standard in vitro susceptibility testing is reputedly problematic due to the inaccurate results obtained and, in compliance with the National Committee for Clinical Laboratory Standards (NCCLS) guidelines, agar dilution testing remains the method of choice. Despite initial susceptibility, drug resistance may develop under treatment conditions with β-lactam antibiotics, quinolones or aminoglycosides in normal dosing regimens.2 This has prompted the in vitro evaluation of combinations of different antibiotics. In the time–kill method, ticarcillin– clavulanate in combination with either trimethoprim– sulphamethoxazole or ciprofloxacin, and ceftazidime with ciprofloxacin were assessed as acting synergistically.3 In this study, 2 g ceftazidime (GlaxoWellcome, Hamburg, Germany), 400 mg ciprofloxacin (Bayer, Leverkusen, Germany) and 1 g meropenem (Astra-Zeneca, Plankstadt,
Germany) were each administered intravenously and separately as a single dose to six healthy volunteers (mean age 22 years; range 20–24 years) with a 1 week interval between the different antibiotics. Serum samples were taken from the volunteers 1 and 4 h after administration of each antibiotic and pooled immediately. MICs for 10 clinical isolates of S. maltophilia were determined by the agar dilution method according to the recommendations of the NCCLS. According to the breakpoints, all strains were found to be susceptible to ceftazidime (MIC range: 2–4 mg/L) and ciprofloxacin (MIC range: 0.5–1 mg/L) but to be resistant to meropenem (MICs 16 mg/L). Serum drug concentrations in pooled sera (1 and 4 h) were measured by HPLC. Concentrations after 1 and 4 h, respectively, were 82 and 18.4 mg/L for ceftazidime, 5.6 and 2.7 mg/L for ciprofloxacin, and 22.2 and 2 mg/L for meropenem. Serum bactericidal activity (SBA) was determined by a microdilution technique. Sera were diluted (1:2–1:64) in cation-supplemented Mueller–Hinton broth. The serum bactericidal titre was defined as the highest dilution of a pooled serum sample that killed 99.9% of the final inoculum of 105 cfu/mL S. maltophilia. Bactericidal titres of 10 isolates ranged at 1 h (4 h) between 1:2 and 1:8 (1:2) and between 1:2 and 1:4 (1:2) for ceftazidime and ciprofloxacin, respectively. Reciprocal serum bactericidal geometric mean titres for ceftazidime were 3.24 and 1.23 and for ciprofloxacin, 1.32 and 1.07, after 1 and 4 h, respectively. Meropenem showed no bactericidal activity against S. maltophilia at a 1:2 dilution (negative control). It is generally accepted that a reciprocal serum bactericidal peak titre of 8 correlates with a favourable clinical outcome in the treatment of Gram-negative infections,4 whereas in the present investigation a relatively low SBA of ceftazidime and ciprofloxacin was documented. Therefore, higher drug concentrations may be necessary for better bacterial killing. To evaluate this hypothesis, the SBA of high concentrations of ceftazidime and ciprofloxacin against S. maltophilia was determined in vitro. Concentrations of ceftazidime (0.31–320 mg/L) and ciprofloxacin (0.31–10 mg/L) were assayed using the SBA methodology. The concentrations of 160 mg/L ceftazidime and of 5 mg/L ciprofloxacin were bactericidal against all 10 isolates tested (Table). A high dosing regimen with 300 mg/kg/day (maximum daily dose up to 12 g) of ceftazidime yielded serum concentrations of 350 mg/L as described by David & Devlin.5 Oral ciprofloxacin was given to 50 patients in a maximum daily dose of 1500 mg/day for the treatment of cystic fibrosis.6 Tolerability of both antibiotics in these high concentrations is well documented and intensive clinical and
118 © 2001 The British Society for Antimicrobial Chemotherapy
Correspondence Table. Serum bactericidal activity of ceftazidime and ciprofloxacin against 10 S. maltophilia isolates Ceftazidime (mg/L) 320 160 80 40 20 10 5 2.5 1.25 0.63 0.31
Killed strains (%)
Ciprofloxacin (mg/L)
Killed strains (%)
10 (100) 10 (100) 9 (90) 7 (70) 6 (60) 5 (50) 5 (50) 4 (40) 1 (10) 1 (10) 0
10 5 2.5 1.25 0.63 0.31
10 (100) 10 (100) 9 (90) 3 (30) 0 0
laboratory monitoring revealed no drug-related toxicity.6 In conclusion, 2 g ceftazidime and 400 mg ciprofloxacin showed a limited SBA against drug-sensitive strains of S. maltophilia. Meropenem was not active against S. maltophilia and exhibited no SBA. The results of this study suggest that the bactericidal activity against S. maltophilia infections can be improved by increasing ceftazidime and ciprofloxacin to high doses. Thus, for the treatment of S. maltophilia infection with a known susceptibility pattern, it may be prudent to use ceftazidime or ciprofloxacin at the maximum tolerated doses as monotherapy. Particularly in patients with multiple organ dysfunction, a low extent of drug related toxicity is of great benefit. Evaluation of these results in vivo may be warranted.
References 1. Vartivarian, S., Anaissie, E., Bodey, G., Sprigg, H. & Rolston, K. (1994). A changing pattern of susceptibility of Xanthomonas maltophilia to antimicrobial agents: implications for therapy. Antimicrobial Agents and Chemotherapy 38, 624–7.
2. Garrison, M. W., Anderson, D. E., Campbell, D. M., Carroll, K. C., Malone, C. L., Anderson, J. D. et al. (1996). Stenotrophomonas maltophilia: Emergence of multidrug-resistant strains during therapy and in an in vitro pharmacodynamic chamber model. Antimicrobial Agents and Chemotherapy 40, 2859–64. 3. Poulos, C. D., Matsumura, S. O., Willey, B. M., Low, D. E. & McGeer, A. (1995). In vitro activities of antimicrobial combinations against Stenotrophomonas (Xanthomonas) maltophilia. Antimicrobial Agents and Chemotherapy 39, 2220–3. 4. Syrogiannopoulos, G. A. & Nelson, J. D. (1988). Duration of antimicrobial therapy for acute suppurative osteoarticular Infections. Lancet 1, 37–40. 5. David, T. J. & Devlin, J. (1989). Continuous infusion of ceftazidime in cystic fibrosis. Lancet 1, 1454–5. 6. Schaad, U. B., Wedgwood-Krucko, J., Guenin, K., Buehlmann, U. & Kraemer, R. (1989). Antipseudomonal therapy in cystic fibrosis: aztreonam and amikacin versus ceftazidime and amikacin administered intravenously followed by oral ciprofloxacin. European Journal of Clinical Microbiology and Infectious Diseases 8, 858–65.
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