Experimental study of teicoplanin, alone and in combination, in the therapy of cephalosporin-resistant pneumococcal meningitis.
OBJECTIVE
The aim of the study was to determine the efficacy of teicoplanin, alone and in combination with ceftriaxone, in a rabbit model of cephalosporin-resistant pneumococcal meningitis, and to assess the effect of concomitant therapy with dexamethasone.


METHODS
In vitro killing curves of teicoplanin, with and without ceftriaxone, were performed. Groups of eight animals per treatment were inoculated with a cephalosporin-resistant pneumococcal strain (penicillin MIC, 4 mg/L; ceftriaxone MIC, 2 mg/L; teicoplanin MIC, 0.03 mg/L) and treated over a 26 h period. Teicoplanin was administered at a dose of 15 mg/kg, alone and in combination with ceftriaxone at 100 mg/kg with or without dexamethasone at 0.25 mg/kg. CSF samples were collected at different time-points, and bacterial titres, white blood cell counts, lactate and protein concentrations and bacteriostatic/bactericidal titres were determined. Blood and CSF teicoplanin pharmacokinetic and pharmacodynamic parameters were determined.


RESULTS
Teicoplanin alone promoted a decrease in bacterial counts at 6 h of -2.66 log cfu/mL and was bactericidal at 24 h, without therapeutic failures. Similar good results were obtained when dexamethasone was used simultaneously, in spite of the penetration of teicoplanin into the CSF being significantly reduced, from 2.31% to 0.71%. Teicoplanin and ceftriaxone combinations were synergic in vitro, but not in the meningitis model.


CONCLUSIONS
Teicoplanin alone was very effective in this model of cephalosporin-resistant pneumococcal meningitis. The use of concomitant dexamethasone resulted in lower CSF teicoplanin levels, but not in therapeutic failures. The combination of teicoplanin plus ceftriaxone and dexamethasone might be a good alternative for the empirical therapy of pneumococcal meningitis. Additional data should confirm our experiments, in advance of clinical trials to assess efficacy in humans.
Fernández
A
A
Laboratory of Experimental Infection, Infectious Diseases Service and Microbiology Service, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain.
Cabellos
C
C
Tubau
F
F
Maiques
J M
JM
Doménech
A
A
Ribes
S
S
Liñares
J
J
Viladrich
P F
PF
Gudiol
F
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use*; D018550:Cephalosporin Resistance; D015169:Colony Count, Microbial; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D017334:Teicoplanin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D017334:Teicoplanin; D002443:Ceftriaxone; D003907:Dexamethasone