JAC Advance Access originally published online on April 14, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Journal of Antimicrobial Chemotherapy (2003) 51, 1308-1309
© 2003 The British Society for Antimicrobial Chemotherapy
Correspondence |
Reply
Service des Maladies Infectieuses, EA 562 - LQRF, Hôpital du Bocage, BP 1542, 21034 Dijon, France
Keywords: levofloxacin, Streptococcus pneumoniae, pneumonia, model
Sir,
We thank Professor Rubinstein1 for providing us with the opportunity to clarify some points about our human-like model of pneumococcal pneumonia.
Our model is, in fact, not a very new one, since it was first mentioned in 19132 and has been used recently by others.3 The 1010 cfu/mL inoculum employed to induce the pneumonia seems to be high, but is lower than that used in other animal models when the weight of the animal is taken into consideration.4–6 This concentration of inoculum has also been applied by others, in rabbit models of Pasteurella multocida7 and Pseudomonas aeruginosa experimental pneumonia.8 Whatever the inoculum used, our model reproduces the pulmonary bacterial concentration observed in human pneumococcal pneumonia, which reaches 1010–1012 cfu/g.9,10 Professor Rubinstein suggests that the bacterial inoculum can spill over from one lung to another. This is unlikely, since the volume is very small (0.5 mL). The model we use is an extensive multilobar bacteraemic pneumonia, and has been described previously.11
In our paper, we did not state that the pulmonary bacterial concentration at the start of treatment (4 h after inoculation) was around 106 cfu/g, which is the same order of magnitude as that described previously.11 Although it would have been interesting to perform bacterial counts during therapy at fixed intervals, these experiments require a large number of animals, are very costly and would not have contributed to the overall conclusions. No resistant mutants were detected among rabbits that died spontaneously during the first day of treatment (data not shown).
As noted in our article (Figure 3b), levofloxacin is highly effective in the spleen of treated rabbits. In the case of treated rabbits infected with the fully susceptible strain, the bacterial load was 1.4 log10 cfu/g, compared with 3.16 log10 cfu/g in untreated animals. These findings establish the positive control for the experiment. The treatment administered to the rabbits reproduces the human pharmacokinetics of levofloxacin. For the therapeutic evaluation, the rabbits were sacrified at the end of the second day of treatment. In addition, the sacrifice was delayed for 2 h to avoid any carryover effect. Although only the unbound antibiotic fraction is active and used to set comparisons between drugs, the total concentrations are used in clinical practice. We chose to evaluate the treatment after 48 h mainly because most of the international guidelines for clinical practice recommend a re-evaluation of antibiotic treatments at this time point. It would have been interesting to investigate the tissue antibiotic concentration, but technical problems were encountered during preliminary experiments in our laboratory.12
Thus, we consider that our system is a valid model of extensive bacteraemic pneumococcal pneumonia, and can be used to anticipate clinical situations, such as those highlighted by Davidson et al.13 concerning failures of levofloxacin treatment in pneumococcal infection.
Footnotes
* Corresponding author. Tel: +33-3-80-29-33-05; Fax: +33-3-80-29-36-38; E-mail: pascal.chavanet{at}chu-dijon.fr 
References
1
.
Rubinstein, E. (2003). Reply to: Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones. Journal of Antimicrobial Chemotherapy 51, 1307–8.
2 . Winternitz, M. & Hirschfelder, A. (1913). Studies upon experimental pneumonia in rabbits. Journal of Experimental Medicine 17, 657–65.[CrossRef][Web of Science]
3 . Zaitseva, N. (1992). An electron microscopic study and the morphofunctional status of the lungs in an experimental reproduction of acute pneumonia. Vrachebnoe Delo 7, 64–5.
4
.
Ellbogen, M., Olsen, K., Gentry-Nielsen, M. & Preheim, L. (2003). Efficacy of liposome-encapsulated ciprofloxacin compared with ciprofloxacin and ceftriaxone in a rat model of pneumococcal pneumonia. Journal of Antimicrobial Chemotherapy 51, 83–91.
5 . Frimodt-Moller, N., Bentzon, M. & Thomsen, V. (1986). Experimental infection with Streptococcus pneumoniae in mice: correlation of in vitro activity and pharmacokinetic parameters with in vivo effect for 14 cephalosporins. Journal of Infectious Diseases 154, 511–7.[Web of Science][Medline]
6 . Gavalda, J., Capdevila, J. A., Almirante, B., Otero, J., Ruiz, I., Laguarda, M. et al. (1997). Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats. Antimicrobial Agents and Chemotherapy 41, 795–801.[Abstract]
7 . Percy, D. H., Bhasin, J. L. & Rosendal, S. (1986). Experimental pneumonia in rabbits inoculated with strains of Pasteurella multocida. Canadian Journal of Veterinary Research 50, 36–41.
8
.
Wiener-Kronish, J. P., Sakuma, T., Kudoh, I., Pittet, J., Frank, D., Dobbs, L. et al. (1993). Alveolar epithelial injury and pleural empyema in acute P. aeruginosa pneumonia in anesthetized rabbits. Journal of Applied Physiology 75, 1661–9.
9 . Frisch, A., Tripp, J., Barrett, C. & Pidgeon, B. (1942). The specific polysaccharide content of pneumonic lungs. Journal of Experimental Medicine 76, 505–10.[Abstract]
10 . Knapp, B. & Kent, T. (1968). Postmortem lung cultures. Archives of Pathology 85, 200–3.[Web of Science][Medline]
11
.
Piroth, L., Martin, L., Coulon, A., Lequeu, C., Duong, M., Buisson, M. et al. (1999). Development of a new experimental model of penicillin-resistant Streptococcus pneumoniae pneumonia and amoxicillin treatment by reproducing human pharmacokinetics. Antimicrobial Agents and Chemotherapy 43, 2484–92.
12 . Nix, D. (1998). Intrapulmonary concentrations of antimicrobial agents. Infectious Disease Clinics of North America 12, 631–46.[Web of Science][Medline]
13
.
Davidson, R., Cavalcanti, R., Brunton, J., Bast, D., de Azvedo, J., Kibsey, P. C. et al. (2002). Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. New England Journal of Medicine 346, 747–50.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||