Evaluation of the adequacy of the antimicrobial therapy of invasive Haemophilus influenzae infections: A pharmacokinetic/pharmacodynamic perspective.

INTRODUCTION: In Europe, non-typeable H. influenzae (NTHi) is the leading cause of invasive H. influenzae disease in adults and is associated with high mortality. The goal of this study was to determine whether current antimicrobial treatments for H. influenzae infection in Spain are suitable based on their probability of achieving pharmacokinetic/pharmacodynamic (PK/PD) targets. METHODS: Pharmacokinetic parameters for the antibiotics studied (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) and susceptibility data for H. influenzae were obtained from literature. A Monte Carlo simulation was used to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and a specific microorganism population. RESULTS: Regardless of dosing regimen, all antibiotics yielded CFR values of 100% or nearly 100% for all strains, including BL+, BL- and BLNAR, except amoxicillin and ampicillin for BL+. Thus, if an infection is caused by BL+ strains, treatment with amoxicillin and ampicillin has a high probability of failure (CFR≤8%). For standard doses of amoxicillin, amoxicillin/clavulanic acid and imipenem, PK/PD breakpoints were consistent with EUCAST clinical breakpoints. For the other antimicrobials, PK/PD breakpoints were higher than EUCAST clinical breakpoints. CONCLUSIONS: Our study confirms by PK/PD analysis that, with the antimicrobials used as empirical treatment of invasive H. influenzae disease, a high probability of therapeutic success can be expected.

Susceptibility of Pseudomonas aeruginosa and antimicrobial activity using PK/PD analysis: an 18-year surveillance study.

INTRODUCTION: We analysed the changes in the susceptibility of Pseudomonas aeruginosa to antimicrobials over an 18-year period (2000-2017) in order to evaluate the adequacy of the antimicrobial therapy against this organism in patients admitted in a tertiary Spanish hospital (excluding the intensive care unit). In addition, the antimicrobial activity was evaluated using pharmacokinetic/pharmacodynamic (PK/PD) criteria as a microbiological surveillance tool. METHODS: Susceptibility was studied according to the Clinical and Laboratory Standards Institute breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. RESULTS: In 2017, susceptibility rates were: amikacin, penicillins and cephalosporins ≥85%, tobramycin 76%, meropenem 75% and gentamicin, imipenem and fluoroquinolones <70%. PK/PD analyses was able to identify changes in antimicrobial activity not detected by only assessing MICs; meropenem administered in extended infusion attained a CFR >90%, ceftazidime, piperacillin/tazobactam and imipenem provided CFRs between 80-90%, all of them administered at the highest doses. CONCLUSIONS: Analysis of susceptibility and PK/PD modelling, should be considered together to select the most appropriate antimicrobial drug and dosage regimen. Empirical antipseudomonal therapy would vary considerably if both microbiological surveillance tools were considered. In this study, the PK/PD analysis made it possible to preserve the therapeutic value of antimicrobials with low susceptibility rates, such as carbapenems, and the selection of the most effective antimicrobials among those with high rates of susceptibility.

Pharmacokinetic/pharmacodynamic evaluation of antimicrobial treatments of orofacial odontogenic infections.

OBJECTIVE: To evaluate the efficacy of antimicrobial therapy in oral odontogenic infections using estimated pharmacokinetic/pharmacodynamic parameters or efficacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints with National Committee for Clinical Laboratory Standards' (NCCLS) breakpoints. STUDY DESIGN: Retrospective literature search to obtain minimum inhibitory concentration (MIC) values, pharmacokinetic parameters of antimicrobials and NCCLS breakpoints. Pharmacokinetic simulations were carried out using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA). METHODS: For antimicrobials with time-dependent activity, the time that the plasma drug concentration exceeds the MIC as the percentage of dose interval at steady state was calculated. For antimicrobials with concentration-dependent activity, the total area under the plasma concentration-time curve over 24 hours at steady state divided by the MIC was calculated. Pharmacokinetic/pharmacodynamic breakpoints were calculated according to these parameters. RESULTS: Only amoxicillin/clavulanic acid and clindamycin showed adequate efficacy indices against the most commonly isolated bacteria in odontogenic infections. Metronidazole reached good indices against anaerobes only. Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide exactly with NCCLS breakpoints. CONCLUSION: Owing to the scarcity of double-blind, clinical trials on the use of antimicrobials in endodontics, this study may be useful in determining the best antimicrobial treatment in these infections. However, as we have not used concentration data in infected tissue to determine pharmacokinetic/pharmacodynamic indices, it would be necessary to design clinical trials in order to confirm these results.