Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

There is strong evidence in literature supporting the benefit of monitoring plasma concentrations of β-lactam antibiotics in the critically ill to ensure appropriateness of dosing. The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6. μm, 2.1. ×. 50. mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control samples (QCs) ranging from 95 to 107% and 95 to 108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12% and 5 to 14%, respectively. The lower limit of quantification was 0.1. μg/mL for each antibiotic except flucloxacillin (0.25. μg/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected β-lactam antibiotics

Multidrug-resistant Acinetobacter baumannii infections: current evidence on treatment options and role of PK/PD in dose optimization

Acinetobacter baumannii remains a difficult-to-treat pathogen that poses a significant challenge to clinicians and cost to the healthcare system. There is a lack of clinical efficacy data to aid in the selection of optimal treatment for multi-drug resistant (MDR) A. baumannii infections. This paper aims to review recent literature on the treatment of MDR A. baumannii and novel agents in the pipeline and discuss the clinical data supporting their use. Colistin has been widely studied as monotherapy or as part of combination therapy, but its use is limited due to nephrotoxicity. The clinical benefit of combination therapy, whether empirical or targeted, has yet to be demonstrated, due to a lack of definitive evidence from randomized controlled trials. Most available clinical studies are retrospective and lack control groups, which offers low-grade evidence. Novel agents such as cefiderocol, plazomicin, eravacycline, and sulbactam/ETX2514 combination are promising options for the treatment of different infection pathologies caused by MDR A. baumannii, but these have yet to be evaluated in randomized controlled trials. A better understanding of the pharmacokinetics (PK)/pharmacodynamics (PD) of the "old" antibiotics is required to optimize their dosing regimens to maximize bacterial killing, minimize toxicities and improve clinical outcomes

Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae. In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates

An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units

Objectives Emerging evidence supports the use of therapeutic drug monitoring (TDM) of β-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for β-lactam TDM in ICUs. Methods A questionnaire survey was developed to describe various aspects relating to the conduct of β-lactam TDM in an ICU setting. Data sought included: β-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. Results Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the β-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of β-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4×MIC) and dose adjustment strategies used by each of the sites. Conclusions Large variations were found in the type of β-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing β-lactam dosing with TD

Challenges in antifungal therapy in diabetes mellitus

Diabetic patients have an increased propensity to Candida sp. infections due to disease-related immunosuppression and various other physiological alterations. The incidence of candidiasis has increased in number over the years and is linked to significant morbidity and mortality in critically ill and immunosuppressed patients. Treatment of infection in diabetic patients may be complicated due to the various disease-related changes to the pharmacokinetics and pharmacodynamics (PK/PD) of a drug, including antifungal agents. Application of PK/PD principles may be a sensible option to optimise antifungal dosing regimens in this group of patients. Further studies on PK/PD of antifungals in patients with diabetes mellitus are needed as current data is limited or unavailabl

Does beta-lactam pharmacokinetic variability in critically ill patients justify therapeutic drug monitoring? A systematic review

The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When "standard" beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of betalactam therapeutic drug monitoring (TDM) and individualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required

Solid nanoparticles for oral antimicrobial drug delivery: a review

Most microbial infectious diseases can be treated successfully with the remarkable array of antimicrobials current available; however, antimicrobial resistance, adverse effects, and the high cost of antimicrobials are crucial health challenges worldwide. One of the common efforts in addressing this issue lies in improving the existing antibacterial delivery systems. Solid nanoparticles (SNPs) have been widely used as promising strategies to overcome these challenges. In addition, oral delivery is the most common method of drug administration with high levels of patient acceptance. Formulation into NPs can improve drug stability in the harsh gastrointestinal (GI) tract environment, providing opportunities for targeting specific sites in the GI tract, increasing drug solubility and bioavailability, and providing sustained release in the GI tract. Here, we discuss SNPs for the oral delivery of antimicrobials, including solid lipid NPs (SLNs), polymeric NPs (PNs), mesoporous silica NPs (MSNs) and hybrid NPs (HNs). We also highlight a range of nanocarrier-based approaches for antimicrobials [modification of existing antimicrobials, enhancing drug-loading content and efficiency, increasing stability, and intravenous (IV)-oral antimicrobials], challenges, clinical transformation, and limitations of SNPs for oral antimicrobial drug delivery

Pharmacodynamic Evaluation of a Single Dose versus a 24-Hour Course of Multiple Doses of Cefazolin for Surgical Prophylaxis

The optimal perioperative duration for the administration of cefazolin and other prophylactic antibiotics remains unclear. This study aimed to describe the pharmacodynamics of cefazolin for a single 2 g dose versus a 24 h course of a 2 g single dose plus a 1 g eight-hourly regimen against methicillin-susceptible Staphylococcus aureus. Static concentration time–kill assay and a dynamic in vitro hollow-fibre infection model simulating humanised plasma and interstitial fluid exposures of cefazolin were used to characterise the pharmacodynamics of prophylactic cefazolin regimens against methicillin-sensitive Staphylococcus aureus clinical isolates. The initial inoculum was 1 × 105 CFU/mL to mimic a high skin flora inoculum. The static time–kill study showed that increasing the cefazolin concentration above 1 mg/L (the MIC) did not increase the rate or the extent of bacterial killing. In the dynamic hollow-fibre model, both dosing regimens achieved similar bacterial killing (~3-log CFU/mL within 24 h). A single 2 g dose may be adequate when low bacterial burdens (~104 CFU/mL) are anticipated in an immunocompetent patient with normal pharmacokinetics