β-Lactam Activity against Penicillin-Resistant <i>Streptococcus pneumoniae</i> Strains Exhibiting Higher Amoxicillin versus Penicillin Minimum Inhibitory Concentration Values: An in vitro Pharmacodynamic Simulation

Abstract

Background: Activity of simulated serum concentrations after oral therapy with 400 mg cefditoren pivoxil b.i.d., 500 mg cefuroxime axetil b.i.d. and 875/125 mg amoxicillin/clavulanic acid b.i.d. and t.i.d. regimens was explored over 24 h against Streptococcus pneumoniae.Methods: Computerized pharmacodynamic simulations were performed against strains with penicillin/amoxicillin/cefuroxime/cefditoren minimum inhibitory concentrations (MICs, µg/ml) and serotypes: strain 1 (0.25/0.12/1/0.12; serotype 6A), strain 2 (2/4/ 2/0.25; serotype 6B), strain 3 (4/16/4/0.5; serotype 14), and strain 4 (4/16/8/1; serotype 14). Results: Bactericidal activity (≧3 log₁₀ reduction) at 12 and 24 h was obtained against all strains with cefditoren, against strains 1 and 2 with cefuroxime and amoxicillin/clavulanic acid t.i.d., but only against strain 1 with amoxicillin/clavulanic acid b.i.d.. Bactericidal activity at 24 h was related to T > MIC of >30% dosing interval, 1.7–2.0 log₁₀ reductions with T > MIC of 20–30%, and <1 log₁₀ reduction or regrowth with T > MIC of 0%. Conclusions: It is difficult to achieve pharmacodynamic coverage and bactericidal activity by physiological concentrations of oral β-lactams against penicillin-resistant pneumococcal strains exhibiting higher amoxicillin versus penicillin MICs. Cefditoren may offer alternatives.

Decreased Streptococcus pneumoniae susceptibility to oral antibiotics among children in rural Vietnam: a community study

“…According to pharmacokinetic-pharmacodynamic principles, the appropriate dose of amoxicillin is the one that maximizes the time when the plasma concentration persists above the MICs of the etiological agent (t > MIC) [43]. For that reason, the aim is to increase the t > MIC by increasing the number of daily doses to achieve bactericidal activity against isolates with MIC ≥ 2 mg/l [18,20,44]. To assure the therapeutic effect for at least 95% of pneumococcal infections in the context, the recommended dose of amoxicillin at 25 mg/kg × 3 times daily thus appears to be too low [32,42,44].…”

“…For that reason, the aim is to increase the t > MIC by increasing the number of daily doses to achieve bactericidal activity against isolates with MIC ≥ 2 mg/l [18,20,44]. To assure the therapeutic effect for at least 95% of pneumococcal infections in the context, the recommended dose of amoxicillin at 25 mg/kg × 3 times daily thus appears to be too low [32,42,44]. The guidance to increase the dose needs to be further demonstrated by clinical research.…”

Cefuroxime for Empiric Treatment of Community-Acquired Pneumococcal Pneumonia: Is There a Generation Gap?

“…As shown in our microbiologic results, no isolates had an MIC of greater than 2 g/ml. Sevillano et al [26] , using a pharmacodynamic simulation model, demonstrated bactericidal activity of oral cefuroxime for strains of S. pneumoniae with MIC of 2 g/ml. Mandell et al [27] , in revised guidelines for management of community-acquired pneumonia, lists cefuroxime as acceptable treatment for S. pneumoniae not resistant to penicillin (MIC !…”

Multi‐drug resistance in Streptococcus pneumoniae among children in rural Vietnam more than doubled from 1999 to 2014

“…29 For that reason, the aim is to increase the t > MIC condition by increasing the number of daily doses in order to achieve bactericidal activity against isolates with an MIC of >2 mg/L. 14,15,30 To assure that the therapeutic effect is achieved for at least 88% of pneumococcal infections in this context, the…”