Potential antagonism between bactericidal β-lactam antibiotics and bacteriostatic antibiotics in an in vitro pharmacodynamic model of septic shock

Abstract

Abstract Background Septic shock caused by bacterial infections continues to be one of the main causes of death in the Intensive Care Units (ICU) of developed countries. Staphylococcus aureus and Escherichia coli are commonly isolated in septic individuals. Improving the outcome of septic shock has focused on accelerating microbiological burden clearance by using more potent antibacterials, optimization of pharmacokinetics and evaluating the additive and synergistic effects of combination therapy of antibiotics (AB). Objective This study assesses the antibacterial potency of a bactericidal β-lactam combined with a bacteriostatic agent against sensitive gram-positive and gram-negative bacteria in both a time kill assay and an in vitro pharmacodynamic assay. These combinations of ABs are routinely administered to septic shock ICU patients. Methods Antibacterial susceptibility testing, TK assays, single and multiple drug IVPD assays were used to determine the effect of AB combinations on the rate of bacterial killing. Specifically, cefazolin with erythromycin or clindamycin against S. aureus clinical isolate 118324 and ceftriaxone with tigecycline or chloramphenicol against E. coli ATCC 700973 Serotype O18:K1:H7 in cation adjusted Mueller-Hinton broth.

Results S. aureus was susceptible to cefazolin, clindamycin and erythromycin with MIC’s equal to 0.5, 0.5 and 1 µg/ml respectively. E. coli was susceptible to ceftriaxone, tigecycline and chloramphenicol with MIC’s equal to 0.03, 0.25 and 8 µg/ml respectively. E. coli TK results showed antagonism after 12-hours of drug exposure, for combinations of ceftriaxone with tigecycline or chloramphenicol. S. aureus TK results showed antagonism by 12- and 24-hours for combinations of cefazolin with clindamycin or erythromycin. The results of E. coil and S. aureus IVPD assays demonstrated antagonism as well as a decrease in bacterial killing rate when a β-lactam was given in combination with a protein synthesis inhibitor. Conclusion This study demonstrated that clinically relevant serum concentrations of a β-lactam in combination with a bacteriostatic protein synthesis inhibitor, resulted in a reduced rate of bacterial killing for both E. coli and S. aureus in both TK and IVPD assays. A reduction in the rate of killing of pathogens could play an important role in clinical treatment for delay sensitive conditions such as septic shock.