Relationship of Minimal Inhibitory Concentration and Bactericidal Activity to Efficacy of Antibiotics for Treatment of Ventilator-Associated Pneumonia

Abstract

Although minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) have been used as the most popular prediction tools for antimicrobial action, they have shortcomings. The MIC and MBC do not consider time-related antimicrobial effects, such as killing rate and postantibiotic effect. In this regard, the concept of pharmacokinetic and pharmacodynamic (PK/PD) modeling has been introduced to help interpret determinations of susceptibility breakpoints. Although area under the inhibitory concentration-time curve (AUIC) can be used as a universal PK/PD parameter, target magnitudes of the parameter have to be high enough to exert rapid bactericidal activity (> 250) and to prevent selection and induction of resistance (> 100). For vancomycin used in treatment of methicillin-resistant Staphylococcus aureus pneumonia, a much higher AUIC (400) is suggested to avoid treatment failure. For resistant gram-negative bacteria, such as Pseudomonas aeruginosa, the usual dosage of fourth-generation cephalosporins, carbapenems, and fluoroquinolones cannot achieve the target AUICs. Either combination therapy or higher dosage should be administered to achieve target AUICs and prevent the potential for failure. Unresolved issues, such as influence of protein binding, PK/PD at tissue sites versus blood, the impact of the immune system, should be addressed to refine the applicability of PK/PD in antibiotic treatment.

In vivo development of antimicrobial resistance in Pseudomonas aeruginosa strains isolated from the lower respiratory tract of Intensive Care Unit patients with nosocomial pneumonia and receiving antipseudomonal therapy

“…As anticipated from previous recent studies [38,39,45] Table 1) as well as the frequent use of combinations were actually expected to decrease the risk of emergence of resistance and/or selection of less susceptible subpopulations [16,[26][27][28][46][47][48]. For obvious ethical reasons, a study in which a significant proportion of patients would be treated in a suboptimal fashion is, nowadays, impossible to design in a…”

Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia

“…The PK/PD appropriateness of levofloxacin therapy was assessed by calculating the two most relevant PK/PD indices: the fC max,ss /MIC and the fAUC/MIC ratios [15][16][17][18][19]. There is general consensus that the clinical and microbiological outcomes of fluoroquinolone treatment are favourable and selection of a mutant subpopulation is preventable if an AUC/MIC ≥ 100-125 and a C max,ss /MIC of 10 are achieved in Gram-negative infections [15,[19][20][21][22].…”

“…There is general consensus that the clinical and microbiological outcomes of fluoroquinolone treatment are favourable and selection of a mutant subpopulation is preventable if an AUC/MIC ≥ 100-125 and a C max,ss /MIC of 10 are achieved in Gram-negative infections [15,[19][20][21][22]. For Gram-positive pathogens, the minimum required C max,ss /MIC is also 10, whilst the optimum AUC/MIC target values are still a topic of debate [18,19]. An AUC/MIC of 30-50 is claimed to be optimal in numerous studies performed mainly in in vitro or animal models [23][24][25][26][27][28][29][30].…”

Appropriate Antibiotic Dosage Levels in the Treatment of Severe Sepsis and Septic Shock

“…Pharmacodynamics (PD) relate PKs to the ability of antibiotics to kill or inhibit the growth of micro-organisms [24•]. The parameter that is used to quantify the response of a pathogen to an antimicrobial is the MIC, which represents the antibiotic concentration resulting in inhibition of visible growth under standard conditions [25]. Thus, PD parameters include the time that serum concentrations remain above the MIC (T>MIC), the ratio of the peak concentration to the MIC (C max /MIC) or of the AUC to the MIC (AUC/MIC).…”