Global Antimicrobial Stewardship with a Focus on Low- and Middle-Income Countries.

Antimicrobial resistance is a global public health crisis. Antimicrobial Stewardship involves adopting systematic measures to optimize antimicrobial use, decrease unnecessary antimicrobial exposure and to decrease the emergence and spread of resistance. Low- and middle-income countries (LMICs) face a disproportionate burden of antimicrobial resistance and also face challenges related to resource availability. Although challenges exist, the World Health Organization has created a practical toolkit for developing Antimicrobial Stewardship Programs (ASPs) that will be summarized in this article.

An UHPLC-MS/MS method for the simultaneous determination of ampicillin and sulbactam in human plasma and urine.

BACKGROUND: With few new antibiotics available and an increased prevalence of multidrug-resistant bacteria, optimizing the effectiveness of currently available antibiotics and minimizing the potential for emerging resistance, through PK characterization, is of paramount importance. RESULTS: Inter- and intra-assay results for ampicillin were within 5% for accuracy and 7% for precision, and for sulbactam within 7% for accuracy and 7% for precision, for both plasma and urine. The plasma Cmax was 38.4 µg/ml for ampicillin and 19.0 µg/ml for sulbactam. The urine concentrations were 668 µg/ml for ampicillin and 438 µg/ml for sulbactam. CONCLUSION: An UHPLC-MS/MS method to simultaneously measure co-formulated ampicillin and sulbactam in plasma and urine, for use in a patient PK study, has been developed and validated.

Protein binding of ß-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations?

The use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (P < 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (R(2) = 0.81 to 1.00; P < 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated (R(2) = 0.776; P < 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.

Ampicillin/sulbactam: its potential use in treating infections in critically ill patients.

The purpose of this paper was to review the potential utility of ampicillin/sulbactam (SAM) as a therapy for serious infections in critically ill patients. Data for this review were identified by searches of PubMed and of the reference lists of the included articles. We found that SAM appears to have a number of characteristics that support its use in the treatment of serious infections in critically ill patients. SAM demonstrates extensive penetration into many infection sites, supporting its use in a wide range of infection types. Microbiologically, sulbactam has strong intrinsic antibiotic activity against multidrug-resistant (MDR) bacteria, including Acinetobacter baumannii, which supports its use for the treatment of infections mediated by this pathogen. Of some concern, there have been reports showing a decline in susceptibility of some bacteria to SAM. As such, use of lower doses (4/2g/day), particularly for MDR A. baumannii, has been linked with a 30% reduced success rate in critically ill patients. The therapeutic challenges for ensuring achievement of optimal dosing of SAM result partly from bacterial susceptibility but also from the pharmacokinetic (PK) alterations common to ß-lactam agents in critical illness. These PK changes are likely to reduce the ability of standard dosing to achieve the concentrations observed in non-critically ill patients. Optimisation of therapy may be more likely with the use of higher doses, administration by 4h infusion or by combination therapy, particularly for the treatment of infections caused by MDR pathogens.

Pharmacokinetics of meropenem and piperacillin in critically ill patients with indwelling surgical drains.

Meropenem and piperacillin are two commonly prescribed antibiotics in critically ill surgical patients. To date, the pharmacokinetics of these antibiotics in the presence of indwelling abdominal surgical drains is poorly defined. This was a prospective pharmacokinetic study of meropenem and piperacillin. Serial plasma, urine and surgical drain fluid samples were collected over one dosing interval of antibiotic treatment in ten patients (meropenem, n = 5; piperacillin n = 5). Drug concentrations were measured using a validated high-performance liquid chromatography assay. Median (interquartile range) pharmacokinetic parameter estimates for meropenem were as follows: area under concentration-time curve (AUC), 128.7 mgh/L (95.3-176.7 mgh/L); clearance (CL), 5.7 L/h (5.1-10.5 L/h); volume of distribution (Vd), 0.41 L/kg (0.35-0.56 L/kg); AUC ratio (drain:plasma), 0.2 (0.1-0.2); and calculated antibiotic clearance via surgical drain, 3.8% (2.8-5.4%). For piperacillin, unbound pharmacokinetic results were as follows; AUC, 344.3 mgh/L (341.1-348.4 mgh/L); CL, 13.1 L/h (12.9-13.2 L/h); Vd, 0.63 L/kg (0.38-1.28 L/kg); AUC ratio (drain:plasma), 0.2 (0.2-0.3); and calculated antibiotic clearance via surgical drain 8.2% (3.3-14.0%). A linear correlation was present between the percentage of antibiotic cleared through the drain and the volume of surgical drain fluid output for meropenem (r(2) = 0.89; P = 0.05) and piperacillin (r(2) = 0.63; P = 0.20). Meropenem and piperacillin have altered pharmacokinetics in critically ill patients with indwelling surgical drains. We propose that only when very high drain fluid output is present (>1000 mL/day) would an additional dose of antibiotic be necessary.

Pharmacokinetics of beta-lactam antibiotics in patients with intra-abdominal disease: a structured review.

BACKGROUND AND PURPOSE: The objective of this structured review was to analyze critically the findings of pharmacokinetic studies of beta-lactam antibiotics in patients with intra-abdominal disease; that is, intra-abdominal infection (IAI) or previous abdominal surgery and determine the requirements for dosage modification in this population. METHODS: Data were identified by structured review of PUBMED from February 1983 to February 2011. All 14 articles reviewed described the pharmacokinetics of beta-lactam antibiotics in patients with intra-abdominal disease. RESULTS: Antibiotic classes included carbapenems, penicillins, cephalosporins, and monobactams. Possible physiological changes in these patients include development of abscesses, perforation, or ischemia of the bowel as well as intra-abdominal hypertension. These disorders may cause changes in antibiotic pharmacokinetics, including increased volume of distribution and faster drug clearance, both resulting in lower antibiotic concentrations. High inter-individual pharmacokinetic variability was common to each of the studies. CONCLUSION: Most of the available data demonstrate that drug volume of distribution can be increased significantly in the presence of intra-abdominal disease. Drug clearance is likely to vary in line with renal or hepatic function. Thus, dose optimization is important to prevent development of antibiotic resistance or therapeutic failure. However, further research is necessary to determine the clinical outcome of individualized dosing on the basis of pharmacokinetic/pharmacodynamic studies.