Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers

Abstract

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.

Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria

“…Cefotaxime [12] 1 g q6h Bolus, 0.5-h and 1-h infusion 275.33 ± 50.11 0.207 ± 0.035 -38 2 g q6h Cefepime [22] 1 g q8h Bolus 125 ± 21 0.25 ± 0.04 -20 1 g q12h 2 g q8h 143 ± 25 0.23 ± 0.05 -20 2 g q12h Ertapenem [22] 1 g q12h 0.5-h infusion 29.5 ± 3.4 0.12 ± 0.02 -95 1 g q24h Imipenem [22] 500 mg q8h 0.5-h infusion 175 ± 23 0.22 ± 0.05 -8.7 500 mg q6h 1 g q8h 1 g q6h…”

Genesis of Methicillin‐ResistantStaphylococcus aureus(MRSA), How Treatment of MRSA Infections Has Selected for Vancomycin‐ResistantEnterococcus faecium,and the Importance of Antibiotic Management and Infection Control

“…This principle of coverage has been studied in in vitro models [59, 62,63]; in animal antibiotic. models of infection [57,59]; in healthy volunteers [64,65]; and in patients with nosocomial pneumonia [60,61,66], acute If Selection Is So Common, Why Doesn't Every Patient exacerbations of chronic bronchitis [67], or other infections [68].…”

Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice

“…Blood serum was collected from eight anesthetized CI mice at each time interval after the sixth dose on day 3. To determine the concentration of the antimicrobial agent, serum samples were analyzed by a validated high-performance liquid-chromatography (HPLC) assay with fluorescence detection as described earlier ( Nix et al 1997 ). The lowest detectable concentration of the assay was 0.05 μg/ml LVX.…”