1 Medicines Research Centre, GlaxoSmithKline; 2 Anti-bacterialsMedical Department, GlaxoSmithKline S.p.A., Verona, Italy
Keywords: ß-lactams, in vitro, bactericidal activity, Pseudomonas aeruginosa, drug dosages
Sir,
The time above the minimum inhibitory concentration (t > MIC) is considered to best predict the in vivo activity of ß-lactam antibacterial agents, with administration by continuous infusion (CI) allowing optimization of the t > MIC over a 24 h period.1 Preclinical and clinical evidence indicates that the drug concentration in serum should reach 45 times the MIC value to exert the maximum bactericidal effect during CI.1,2 However, such a value may be hard to reach in infections caused by difficult to treat Gram-negative bacteria, like Pseudomonas aeruginosa. Ceftazidime is one of the more extensively studied drugs that are currently given by CI administration and its clinical efficacy has been confirmed in different patient populations.35 The in vitro study we report here was undertaken to assess the bactericidal activity of different ceftazidime concentrations on either susceptible or resistant P. aeruginosa isolates. All of the study strains were obtained from respiratory samples from patients hospitalized in intensive care units. Six of the P. aeruginosa strains were susceptible (CTZ-S) with MIC values 8 mg/L; four strains were intermediate (MIC = 16 mg/L; CTZ-I) and three strains were resistant (CTZ-R) with MIC values
32 mg/L. MIC values were determined for each of the study strains by the NCCLS methodology.6 Bactericidal activity was defined as a
3 log10 reduction in a 105 cfu/mL inoculum. Bacterial suspensions were prepared from an overnight agar plate culture, then transferred into MuellerHinton broth supplemented with calcium (25 mg/L) and magnesium (12.5 mg/L) and incubated for 2 h at 37°C to reach logarithmic phase. Ceftazidime concentrations of 2 x, 4 x and 8 x MIC as exact multiples of the MIC value were added to the medium and bacterial counts carried out after 0, 4, 6, 8 and 24 h. In order to avoid ceftazidime carry-over, 0.1 mL aliquots were sampled with a detection limit of 10 cfu/mL. All the experiments were repeated two times.
Ceftazidime exerted maximal bactericidal activity within 68 h in all the experiments (Figure 1). Eleven out of 13 strains and 12 out of 13 strains, exposed to 4 x and 8 x MIC, respectively, showed a decrease of more than 3 log10 cfu/mL at 6 h after antibiotic exposure. In the experiments where the strains were exposed to 2 x MIC, a decrease of 2.44.8 log10 cfu/mL was observed after 68 h of antibiotic exposure, even though four (MIC range 432 mg/L) out of 13 strains showed re-growth after 24 h. No variations in the bactericidal activity of ceftazidime could be correlated with the MIC value for the different strains.
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CI has been reported to be at least as effective as intermittent administration in severe infections.35 ß-Lactam clinical efficacy may be optimized using administration by CI providing that serum drug concentrations are in excess of the MIC value of the infecting bacteria. From our results, the use of ceftazidime at a concentration of 4 x MIC gave excellent bactericidal activity within 68 h of antibiotic exposure and increasing the drug concentration to 8 x MIC did not increase the bacterial killing. Ceftazidime concentrations of 2 x MIC still demonstrated in vitro bactericidal activity against P. aeruginosa, but at 68 h after drug exposure, thus supporting the hypothesis that the 2 x MIC value may be sufficient to achieve bacterial killing over a 24 h period. Should such an assumption be confirmed, a reduction in the ceftazidime daily dosage, or treatment of more resistant bacteria, could be introduced. Before any conclusions can be reached as to clinical validity of our findings, the results of the present timekill experiments should be integrated with pharmacokinetic/pharmacodynamic findings and confirmed in clinical trials using different patient sub-populations.
Footnotes
* Corresponding author. Tel: +39-045-9219573; Fax: +39-045-9218043; E-mail: fem75838{at}gsk.com
References
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