Pharmacodynamic Evaluation of Factors Associated with the Development of Bacterial Resistance in Acutely Ill Patients during Therapy

Abstract

The selection of bacterial resistance was examined in relationship to antibiotic pharmacokinetics (PK) and organism MICs in the patients from four nosocomial lower respiratory tract infection clinical trials. The evaluable database included 107 acutely ill patients, 128 pathogens, and five antimicrobial regimens. Antimicrobial pharmacokinetics were characterized by using serum concentrations, and culture and sensitivity tests were performed daily on tracheal aspirates to examine resistance. Pharmacodynamic (PD) models were developed to identify factors associated with the probability of developing bacterial resistance. Overall, in 32 of 128 (25%) initially susceptible cases resistance developed during therapy. An initial univariate screen and a classification and regression tree analysis identified the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC0–24/MIC) as a significant predictor of the development of resistance (P < 0.001). The final PK/PD model, a variant of the Hill equation, demonstrated that the probability of developing resistance during therapy increased significantly when antimicrobial exposure was at an AUC0–24/MIC ratio of less than 100. This relationship was observed across all treatments and within all organism groupings, with the exception of β-lactamase-producing gram-negative organisms (consistent with type I β-lactamase producers) treated with β-lactam monotherapy. Combination therapy resulted in much lower rates of resistance than monotherapy, probably because all of the combination regimens examined had an AUC0–24/MIC ratio in excess of 100. In summary, the selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUC0–24/MIC ratio of less than 100.

BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia

“…The targets were based on prior studies of the PK and pharmacodynamic characteristics of aminoglycosides [12][13][14] and are consistent with the pivotal studies for tobramycin solution for inhalation in cystic fibrosis [14]. We chose a reference MIC of 256 lg/mL because this was the highest amikacin MIC for Pseudomonas aeruginosa and Acinetobacter spp.…”

Extent of storage and wastage of antibacterial agents in Palestinian households

“…Antibacterial agents do not represent a medical risk when used appropriately. However, the frequent and inappropriate use of antibacterial agents might have profound adverse health outcomes for individuals and society [5][6][7][8][9]. Many people tend to store different types of antibacterial agents at home for future self-medication [10].…”

Influence of pharmacokinetic and pharmacodynamic principles on antibiotic selection

“…In vitro, animal and human studies have shown that the pharmacodynamic parameter that best correlates with bacteriological eradication is AUC 24 /MIC (Table 1) [3,6,10,16•,17•,18-22,24]. Further, the pharmacodynamic parameter Cpmax/MIC also correlates with bacteriological eradication and prevention of the development of resistance on therapy (Table 1) [2••,3,10, [19][20][21]. Agents in a third group of antibiotics, including azithromycin, exhibit a time-dependent bacterialkilling pattern and prolonged persistence effects; in vitro and animal studies have shown that AUC 24 /MIC is the parameter best linked to bacteriological eradication and outcome ( …”

“…These authors also have shown that achieving a AUC 24 /MIC ratio of at least 100 is required to prevent the development of resistance on therapy [20].…”

“…Agents in a second group of antibiotics, including fluoroquinolones and aminoglycosides, achieve bacterial killing in a concentration-dependent manner and exhibit prolonged persistence effects [3,6,10,16•,17•, [18][19][20][21][22][23][24][25]. In vitro, animal and human studies have shown that the pharmacodynamic parameter that best correlates with bacteriological eradication is AUC 24 /MIC (Table 1) [3,6,10,16•,17•,18-22,24].…”