Pharmacodynamic Interactions of Antibiotics Alone and in Combination

Abstract

Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacterial killing rates in patients with nosocomial pneumonia and is useful for predicting clinical or microbiological outcomes and making dosage adjustments with beta-lactams, quinolones, aminoglycosides, and vancomycin. The AUIC values of two antibiotics are additive, and since antibiotics are often given in combination, determining the AUIC for antibiotic combinations could potentially predict the microbiological outcomes for patients given these combinations. To further address this question, mathematical modeling was used to study in vitro pharmacokinetic and pharmacodynamic interactions of the antimicrobials piperacillin and ciprofloxacin. These agents were also studied in vivo in healthy volunteers. Blood samples were obtained for analysis of serum drug concentrations, and serum inhibitory titers were determined against eight common bacterial pathogens, chosen to reflect the range of MIC values to ciprofloxacin and piperacillin. Additive AUIC relationships predictive of bacterial killing rates were typical in patients given these antibiotics in combination.

Low-dose β-lactam plus amikacin in febrile neutropenia: cefepime vs. piperacillin/tazobactam, a randomized trial

“…In our trial, the overall resolution of the febrile episode was observed in 92% of cases in both groups, similar to other studies [18][19][20][21][22][23][24][25][26][27][28][29].…”

“…However, lower doses of both antibiotics have been used in some studies [4,9,21,22]. When a combination of agents is used, it is plausible that lower dosing can be administered [23]. In this scenario, the decreased dosage affords the same antibacterial activity and reduces toxicity and pharmacy costs.…”

Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections

“…However, most patients with AUIC values <125 had T>MIC of <100% and did fail (Table 7). Consequently, dosing at a T>MIC of 100% would be a minimal requirement for optimising therapy [15,[25][26][27] as well as providing protection from the emergence of resistance [28].…”

Determinants of Ceftazidime Clearance by Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodialysis

“…Since some clinicians have proposed that the concentrations of cephalosporins in serum only need to exceed the MIC 90 for 40% of the dosage interval, once-a-day administration of the doses in Tables 3 and 4 may be feasible (5). Furthermore, if combination antibiotic therapy is initiated or subsequently added, the desired clinical outcomes may be achieved with an even lower percentage of time above MIC for the cephalosporin (22).…”