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Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to β‐lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about β‐lactam pharmacodynamics (PD) and wide inter‐ and intra‐patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For β‐lactams, the time that free concentrations remain above the minimum inhibitory concentration (MIC) as a function of the dosing interval (%fT>MIC) has been shown to best predict antibacterial effect. Many studies have shown that β‐lactam %fT>MIC exposures are often suboptimal across a wide variety of disease states and clinical settings. A limitation to implementing this practice is the general lack of understanding on how to best operationalize this intervention and interpret the results. The instrumentation and expertise needed to quantify β‐lactams for TDM is rarely available locally, but certain laboratories advertise these services and perform them regularly. Familiarity with the modalities and nuances of antimicrobial susceptibility testing is crucial to establishing β‐lactam concentration targets that meet the relevant exposure thresholds. Evaluation of these concentrations is best accomplished using population PK software and Bayesian modeling, for which a multitude of programs are available. While TDM of β‐lactams has shown an ability to increase the rate of target attainment, there is currently limited evidence to suggest that it leads to improved clinical outcomes. Although consensus guidelines for β‐lactam TDM do not exist in the United States, guidance would help to promote this important practice and better standardize the approach across institutions. Herein, we discuss the basis for β‐lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations. [ABSTRACT FROM AUTHOR]

Methicillin‐resistant Staphylococcus aureus (MRSA) has become the most prevalent cause of acute hematogenous osteomyelitis (AHO) in pediatric patients. This increase in MRSA is due to the rise in community‐acquired MRSA. Therefore, it is important that clinicians are aware of the various and upcoming therapies that cover this bacterium. A literature search of the Medline database was performed from creation through January 2018. Articles chosen for the review emphasize well‐established MRSA treatment options for pediatric AHO, newer therapies on the horizon, and important pharmacokinetics and pharmacodynamic concepts for treatment. Traditional therapies, including vancomycin and clindamycin, remain effective for the treatment of pediatric AHO. When these agents cannot be used, evidence in AHO has been growing for daptomycin, linezolid, and ceftaroline. Further initial pediatric data with the long‐acting lipoglycopeptides show promise and in the future may provide a role in AHO treatment in children. [ABSTRACT FROM AUTHOR]

Acute hematogenous osteomyelitis (AHO), often occurring in young children, is the most frequently diagnosed type of osteomyelitis in pediatric patients. Optimizing antibiotics is essential as delays to receipt of appropriate therapy can lead to chronic osteomyelitis, as well as impairments in bone growth and development. Antimicrobial stewardship programs (ASPs) are in a key position to help improve the care of patients with AHO as they contain a pharmacist with expertise in antibiotic drug selection, optimization of dosing, and microbiologic test review. A literature search of the MEDLINE database was conducted from initiation through January 2018. Articles selected for the review focus on pathogen identification, pharmacokinetics and pharmacodynamics, efficacy and safety in children, transition from intravenous to oral therapy, duration of treatment, and antimicrobial stewardship interventions. This review will highlight the potential roles ASPs can have in improving the management of AHO in pediatric patients. These roles include the creation of clinical pathways, improving testing algorithms, antibiotic choice and dosing, intravenous to oral transitions, duration of treatment, and therapy monitoring. Overall, patients are most effectively treated by focusing treatments on age, presentation, local sensitivities, and directed therapy with pathogen identification. [ABSTRACT FROM AUTHOR]

Limited data are available on ceftolozane/tazobactam dosing in patients receiving continuous renal replacement therapy ( CRRT). Thus we performed a pharmacokinetic analysis of intravenous ceftolozane/tazobactam in a critically ill patient receiving CRRT at our medical center. A 47-year-old critically ill man with multidrug-resistant Pseudomonas aeruginosa pneumonia, bacteremia, and osteomyelitis was receiving ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) every 8 hours while receiving continuous venovenous hemodiafiltration ( CVVHDF). After the fifth dose of ceftolozane/tazobactam, plasma samples were obtained at 1-, 2-, 4-, 6-, and 8-hour time points. Two additional post-hemodialysis filter plasma samples were obtained to assess CVVHDF clearance. The maximum and minimum plasma concentrations for ceftolozane were 163.9 μg/ml and 79.4 μg/ml, respectively. The area under the plasma concentration-time curve from 0-8 hours (AUC0-8) was 689 μg hour/ml; the plasma half-life was 13.3 hours. The ceftolozane CVVHDF clearance and total clearance were 2.4 L/hour and 2.9 L/hour, respectively. Compared with a patient with normal renal function, this patient receiving CVVHDF had decreased ceftolozane clearance. A ceftolozane/tazobactam dosage of 1.5 g every 8 hours should adequately achieve a desired drug concentration above the minimum inhibitory concentration of 8 μg/ml for the treatment of pneumonia. Additional pharmacokinetic data are needed to confirm our results and for alternative forms of CRRT. [ABSTRACT FROM AUTHOR]

Although antimicrobials are commonly used in children, it is important to remember that they can have a profound impact on this unique patient population. Inadvertent consequences of antiinfective use in children include antimicrobial resistance, infection caused by Clostridium difficile, increased risk of obesity, and adverse drug events. In addition, compared with adults, children have different dosing requirements, antimicrobial formulation needs, pharmacokinetics, and antimicrobial susceptibility profiles. Therefore, pediatric-specific antimicrobial stewardship efforts are needed to promote appropriate use of antimicrobials in children. The primary purposes of this review article are to provide a rationale behind pediatric-focused antimicrobial stewardship and to describe currently available evidence regarding the initiatives of pediatric antimicrobial stewardship programs ( ASPs). A literature search of the Medline database was performed (from inception through March 2015). The studies included in this review focus on antimicrobial stewardship interventions in inpatient pediatric settings. Ten inpatient studies involving pediatric-focused antimicrobial stewardship interventions were identified from the published literature. Four studies used the core strategy of prospective audit with feedback; two used prior approval. The remaining four used supplemental antimicrobial stewardship strategies (guidelines, clinical pathways, and computerized decision support tools). In general, the interventions resulted in decreased antimicrobial use, reduced antimicrobial costs, and fewer prescribing errors. Children have unique medical needs related to antimicrobials and deserve focused ASP efforts. The literature regarding pediatric antimicrobial stewardship interventions is limited, but published interventions may serve as paradigms for developing pediatric ASPs as demonstrated by the general success of these interventions. [ABSTRACT FROM AUTHOR]

In the management of multidrug-resistant infections in critically ill patients with multiorgan dysfunction, consideration must be given to the pharmacokinetics and pharmacodynamics of an antimicrobial agent to optimize dosing. We describe a 25-year-old woman who was undergoing thrice-weekly hemodialysis and developed multidrug-resistant Pseudomonas aeruginosa bacteremia secondary to infected left and right ventricular assist devices. After multiple courses of antibiotics, her blood cultures revealed that the infecting organism was becoming progressively more resistant to antibiotic options. Cefepime 2 g administered over 3 hours/day (in combination with colistimethate) provided adequate drug levels for multidrug-resistant, cefepime-intermediate P. aeruginosa bacteremia in this patient. We present the clinical case of this patient, followed by a discussion of possible therapeutic approaches to be considered, including illustration of the principles of using extended-infusion antimicrobial regimens, and present the patient's resulting clinical course. [ABSTRACT FROM AUTHOR]

Study Objective To evaluate and compare the percent protein binding of vancomycin in hospitalized patients by using a clinical or research laboratory-derived assay methodology, and to evaluate potential patient characteristics accounting for alterations in protein binding. Design Prospective noninterventional cohort study. Setting Single-center tertiary care medical center. Patients A total of 55 hospitalized adults who were receiving vancomycin for a suspected or documented infection between August and November 2011 and required therapeutic drug monitoring. Measurements and Main Results Vancomycin protein-binding studies were conducted by using ultracentrifugation of 63 blood samples collected from the 55 patients for therapeutic drug monitoring as part of clinical practice. Total and free drug concentrations were assayed in the research laboratory by using high-performance liquid chromatography ( HPLC) and in the clinical laboratory by using fluorescence polarization immunoassay ( FPIA). Multivariate linear regression analysis was performed to identify patient variables that were predictive of vancomycin protein binding. The average protein binding was statistically significantly lower and more variable when assayed by FPIA compared with HPLC (mean ± SD 47.3 ± 13.0% vs 54.6 ± 9.5%, p<0.001). Multivariate analyses showed that after controlling for days of vancomycin therapy, patients in the intensive care unit ( ICU) had a protein binding value that was 8.4% lower than non- ICU patients (p=0.005). Conclusion Using research laboratory-based HPLC methodology, we identified an average vancomycin protein binding of 54.6% with considerably less variability than reported in the literature using clinical-based assay methodologies. Further, we identified patient factors that may likewise have an impact on this value. Future studies of vancomycin protein binding should consider use of a nonclinical assay to minimize methodological-induced variability. [ABSTRACT FROM AUTHOR]

Study Objective To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5-minute infusion to the standard 30-minute infusion. Design Prospective, randomized, crossover pharmacokinetic study. Setting Clinical research center. Subjects Twelve healthy adult volunteers. Intervention Each subject received ertapenem 1 g intravenously, administered either as a rapid 5-minute infusion or the standard 30-minute infusion, every 24 hours for 3 days (first phase); after a 4-day washout period, each subject then received the other infusion every 24 hours for 3 days (second phase). Measurements and Main Results Plasma samples were collected after the first and third (steady-state) doses of each study phase, and protein binding was assessed by use of ultrafiltration. Pharmacokinetic analyses were conducted using noncompartmental and compartmental methods. A 5000-subject Monte Carlo simulation was used to assess the probability of target attainment for free drug concentration remaining above the minimum inhibitory concentration (MIC) for 40% or greater of the dosing interval (40% fT > MIC) over an MIC range. Ertapenem was well tolerated and adverse events were similar for both infusions. The ertapenem steady-state mean ± SD maximum concentrations were 193.3 ± 43.3 and 165.7 ± 20.4 mg/L for the 5- and 30-minute infusions, respectively; the mean ± SD areas under the concentration-time curves from 0-24 hours were 561.2 ± 77.0 and 531.3 ± 56.9 μg · hr/ml (geometric mean ratio 1.008, 90% confidence interval 0.999-1.017), respectively. Protein binding was concentration dependent (range 87.9-98.9%). A two-compartment model best described ertapenem pharmacokinetics with the following parameter estimates: clearance 1.89 ± 0.19 L/hr, volume of central compartment 5.04 ± 0.56 L, and transfer constants k12 0.43 ± 0.08/hr and k21 0.44 ± 0.07/hr. The probabilities of target attainment for 5- and 30-minute infusions were 97.0% and 97.9% at an MIC of 0.25 mg/L and 1.7% and 2.8% at an MIC of 0.5 mg/L, respectively. Conclusion Ertapenem administered as a rapid 5-minute infusion provides a well tolerated, bioequivalent, and pharmacodynamically equivalent regimen to the 30-minute infusion at clinically relevant MICs. [ABSTRACT FROM AUTHOR]

Study Objective To assess the impact of noncompliance with a ventilator-associated pneumonia ( VAP) computerized clinical pathway ( CCP) on antibiotic use after removal of prospective antibiotic stewardship resources. Design Retrospective, observational, quasi-experimental study. Setting Three intensive care units (medical, surgical, and neurotrauma) in a large, tertiary care hospital. Patients A total of 136 patients with culture-positive VAP; 72 were treated from September 2006- August 2007 (period 1), during which use of the CCP was mandatory along with aggressive stewardship support, and 64 were treated from September 2009- April 2010 (period 2), during which use of the CCP was voluntary. Measurements and Main Results Compliance with use of the CCP was 100% during period 1 and 44% (28/64 patients) during period 2. For the 36 patients (56%) whose antibiotic selection did not comply with the CCP, empiric antibiotics were selected by provider discretion. Most patients had late-onset VAP and were similar with respect to age, sex, and comorbidities between the two periods. Staphylococcus aureus (11-17% methicillin-resistant S. aureus) and Pseudomonas aeruginosa were the most common pathogens during both periods. The proportion of patients with appropriate antibiotics within 24 hours of VAP identification was not significantly different between period 1 (70.8%) and period 2 (56.3%, p=0.112). During period 2, patients who were treated according to the CCP were more likely to receive appropriate antibiotic therapy compared with patients treated according to provider discretion (82.1% vs 36.1%, p≤0.001). Time to appropriate therapy was also shorter for patients treated according to the CCP (mean ± SD 0.43 ± 1.14 vs 1.29 ± 1.36 days, p=0.003). Treatment with the CCP was the only variable significantly associated with appropriate antibiotic therapy (odds ratio 4.8, 95% confidence interval 2.1-10.9). Mortality was not significantly different between period 1 and period 2, and only Acute Physiology and Chronic Health Evaluation II score and admission with a head injury were predictive of death. Finally, a greater proportion of patients treated with the CCP were de-escalated from anti- Pseudomonas β-lactams (85.0% vs 33.3%, p=0.006) when they were not necessary. Conclusion These data highlight the importance of continued stewardship resources after CCP implementation to ensure compliance and to maximize antibiotic stewardship outcomes. [ABSTRACT FROM AUTHOR]

Study Objective. To compare conventional intermittent dosing regimens of piperacillin-tazobactam with prolonged and continuous infusions to determine the optimal dosing scheme against a local Pseudomonas aeruginosa population. Design. Pharmacodynamic Monte Carlo simulation model. Data Source. Microbiologic data from 470 consecutive nonduplicate P. aeruginosa isolates collected from a single institution over 6 months in 2006. Patients. Five thousand simulated surgical patients and patients with neutropenia. Measurements and Main Results. We simulated serum concentration-time profiles at steady state for several piperacillin-tazobactam dosing regimens, including intermittent, prolonged, and continuous infusions. The probability of achieving 50% free time above the MIC against 470 P. aeruginosa isolates was calculated. The cumulative fractions of response for the intermittent-infusion regimens were 74.7% (3.375 g every 6 hrs), 79.9% (4.5 g every 6 hrs), and 85.6% (3.375 g every 4 hrs). For prolongedinfusion regimens, the cumulative fractions of response were 83.3% (3.375 g every 8 hrs, 4-hr infusion), 87.1% (4.5 g every 8 hrs, 4-hr infusion), and 89.6% (4.5 g every 6 hrs, 3-hr infusion). For continuous-infusion regimens, the cumulative fractions of response were 82.3% (10.125 g), 86.5% (13.5 g), 89.2% (18 g), 90.0% (20.25 g), and 90.6% (22.5 g). Conclusion. Both prolonged- and continuous-infusion strategies improved the pharmacodynamics of piperacillin-tazobactam over those of traditional 30-minute intermittent-infusion regimens. Prolonged- and continuousinfusion regimens that contained the same daily doses of piperacillin had similar likelihoods of bactericidal exposure. Thus, the selection of dosing strategy depends on the availability of intravenous access versus the convenience of once-daily administration. [ABSTRACT FROM AUTHOR]

A 31-year-old man with cystic fibrosis was diagnosed with multidrug-resistant Burkholderia cepacia pneumonia. Meropenem 2000 mg every 8 hours was administered as a 3-hour infusion to maximize pharmacodynamic exposure; oral minocycline 100 mg twice/day was also given. Blood samples were collected to confirm meropenem concentrations. Concentrations above the mimimum inhibitory concentration (MIC) of 8 μg/ml were achieved for 52% of the dosing interval, which is greater than what is required for a bactericidal effect. The patient's condition improved, he was discharged, and completed a 3-week course of the antibiotic regimen. After 6 months, he had remained at his baseline level of health. This case demonstrates that pharmacodynamic principles can be used to design an antibiotic dosing regimen that can achieve optimal exposures when the MIC is above that considered susceptible to conventional dosing strategies. [ABSTRACT FROM AUTHOR]

The treatment of gram-negative infection of the central nervous system (CNS) presents a clinical challenge due to antibiotic resistance and difficulties with penetration into the cerebrospinal fluid (CSF). Two patients with gram-negative CNS infections were treated successfully with high-dose, prolonged infusions of meropenem. The CSF meropenem concentrations exceeded the minimum inhibitory concentration of the pathogen for virtually the entire dosing interval in both cases. Our experience demonstrates that dosage modification to maximize pharmacodynamic targets and bactericidal activity may be practically applied to optimize antibiotic treatment for difficult-to-treat CNS infections. [ABSTRACT FROM AUTHOR]

Study Objective. To compare the pharmacodynamics of meropenem and imipenem, both administered as 500 mg every 6 hours, against populations of Enterobacteriaceae, Acinetobacter baumannii. and Pseudomonas aeruginosa. Design. Ten thousand-subject Monte Carlo simulation. Intervention. Variability in total body clearance (Cl[subT]), volume of distribution as calculated by the terminal elimination rate (Vd[subβ]). and minimum inhibitory' concentration (MIC) distributions (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, A. baumannii, P. aeruginosa) were derived from the literature lor both meropenem and imipenem. For the free drug concentrations, the percentage of the dosing interval that the drug concentrations remain above the MIC (%T>MIC) for each carbapenem-bacteria combination was calculated for 10,000 iterations, substituting a different Cl[subT], Vd[subβ], fraction of unbound drug, and MIC into the equation each time based on the probability distribution for each parameter. Probabilities of attaining targets of 30%. 50%. and 100% T>M1C were calculated. Measurements and Main Results. Meropenem free drug %T>M1C exposure was significantly greater than that of imipenem against Enterobacteriaceae and P. aeruginosa. whereas imipenem exposure was greater for A. baumannii. For both agents, free drug %T>M1C exposure was greatest against Enterobacteriaceae and less for A, baumannii and P. aeruginosa. Probabilities of target attainment for 30% and 50% T>MIC were similar between drugs for most bacteria. At 100% T>M1C, meropenem target attainments were greater than those of imipenem against Enterobacteriaceae and P. aeruginosa, and imipenem attainment was higher lor A, baumannii. Conclusion. The probability of attaining lower pharmacodynamic targets for most gram-negative bacteria is similar for these carbapenems; however, differences become apparent as the pharmacodynamic requirement increases. Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary. [ABSTRACT FROM AUTHOR]

Study Objective: To determine the cost-effectiveness of telavancin versus vancomycin for the treatment of complicated skin and skin structure infections (cSSSIs)., Design: Pharmacoeconomic analysis conducted from the hospital's perspective using data from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) phase III clinical trial., Setting: One hundred twenty-nine hospitals in the United States and internationally., Patients: A total of 1044 clinically evaluable patients who were hospitalized with a cSSSI during the ATLAS trial and who received at least one dose of telavancin or vancomycin in the hospital., Measurements and Main Results: Diagnosis-related group-specific hospital bed costs, antibiotic acquisition prices, and cost of vancomycin monitoring were applied to the resource utilization data collected during the ATLAS trial. Infection-related length of stay (LOS(ir)) and hospitalization costs (COST(ir)) were compared between the telavancin (514 patients) and vancomycin (530 patients) groups. Incremental cost-effectiveness ratios (ICERs) were calculated for the total population and a subset of patients infected with methicillin-resistant Staphylococcus aureus (MRSA) by using a 25,000-sample bootstrap analysis. During sensitivity analyses, the daily acquisition price for telavancin was increased from the equivalent to vancomycin ($13.44) to $50, $100, $150, or $200, and the rate of MRSA acquisition was varied between 30% and 75%. The median (interquartile range) LOS(ir) was 8 days (6-12 days) for both telavancin and vancomycin (p=0.742), and median (interquartile range) COST(ir) was $8118 ($6291-11,758) and $8185 ($6474-11,405), respectively (p=0.560). Similar findings were observed for the MRSA subset. Telavancin cost-effectiveness was greater for the MRSA population versus the total population. During bootstrap analyses of the MRSA population, the ICER for telavancin ranged from dominant (-$9560) to $27,889 as acquisition price was increased., Conclusions: Telavancin LOS(ir) and total COST(ir) were similar to those of vancomycin for the treatment of cSSSIs. Particularly in those infected with MRSA, telavancin may be more cost-effective than vancomycin over the range of acquisition prices tested.

Study Objective: To determine the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures against common nosocomial pathogens., Design: Pharmacodynamic Monte Carlo simulation model., Data Source: Microbiologic data generated from isolates from the 14 centers in the United States in the 2004 Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance study., Patients: Five thousand simulated patients with infection., Measurements and Main Results: Pharmacokinetic profiles of the patients were simulated to determine the bactericidal cumulative fraction of response (CFR) for commonly used intravenous regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam against Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella species. Ciprofloxacin and levofloxacin had CFRs among the lowest of all drugs against all pathogens, especially P. aeruginosa (40.4-65.5%) and A. baumannii (43.6-48.2%). The low CFR of about 78% against E. coli with these two agents was of particular concern. Among the beta-lactams, only high-dose cefepime and ceftazidime regimens achieved CFRs of greater than 90% against P. aeruginosa, followed by cefepime 2 g every 12 hours and the carbapenems (86.3-89.7%). No regimen achieved an optimum CFR for A. baumannii. All beta-lactam regimens achieved a greater-than-90% likelihood of having bactericidal CFRs against Enterobacteriaceae., Conclusion: Because of the continual evolution of resistance among gram-negative bacteria in the United States, reevaluation of optimum dosing strategies for beta-lactam and fluoroquinolone antibiotics is necessary.