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Background and Objective: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator. Methods: A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood. Cefiderocol was administered into the circuit to achieve a starting concentration of approximately 90 mg/L. Post-oxygenator blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 h after the addition of the drug to determine the loss in the circuit. A glass control jar was prepared with the same blood matrix and maintained at the same temperature to determine drug degradation. The experiment was conducted in triplicate. The rate of cefiderocol loss in the ECMO circuit was compared with that in the control by one-way analysis of variance. Results: At 0 h, the difference between the pre- and post-oxygenator concentrations was − 4 ± 4% (range 0 to − 7%). After 24 h, the cefiderocol percent reduction was similar between the ECMO circuit and control (50% ± 13 vs. 50% ± 9, p= 1.0). Conclusions: The degradation rate of cefiderocol did not differ significantly within the ECMO circuit and control, suggesting no loss due to sequestration or adsorption. Pharmacokinetic studies in patients supported by ECMO are warranted to determine final dosing recommendations.

Resistant Gram-positive infections present serious challenges to patients and providers who care for them. Ceftaroline is a novel advanced-generation cephalosporin with a broad spectrum of activity against many pathogens. Recently, [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjsurg.2008.11.030 Byline: Kathryn J. Eagye (a), David P. Nicolau (a)(b) Keywords: Elective colorectal surgery; Surgical-site infection; Antibiotic prophylaxis; Health outcomes Abstract: The reported incidence of infection complicating elective colorectal surgery (ECS) is 11% to 26%. We evaluated length of stay (LOS) and expense associated with such infections, which heretofore remain unexplored. Author Affiliation: (a) Center for AntiInfective Research and Development, Hartford Hospital, Hartford, CT, United States (b) Division of Infectious Diseases, Hartford Hospital, Hartford, CT, United States Article History: Received 4 March 2008; Revised 3 November 2008

Serious infections caused by resistant gram-positive cocci continue to increase in prevalence and significance. An NDA for ceftobiprole, an investigational novel broad-spectrum cephalosporin antibiotic, was submitted on May 18, 2007, [...]

Hospital formulary decisions regarding antibiotics are typically made based on the comparative efficacy, safety, and pricing of these agents. Comparative efficacy studies, when available, usually demonstrate equivalence of antibiotics, making [...]

Abstract: Carbapenems are the treatment of choice for extended-spectrum [beta]-lactamases (ESBLs). Ertapenem is a new member of the carbapenem class, and is often grouped with imipenem and meropenem as a [...]

Metallo-β-lactamases (MBLs) result in resistance to nearly all β-lactam antimicrobial agents, as determined by currently employed susceptibility testing methods. However, recently reported data demonstrate that variable and supraphysiologic zinc concentrations in conventional susceptibility testing media compared with physiologic (bioactive) zinc concentrations may be mediating discordant in vitro-in vivoMBL resistance.

Serious fungal infections have emerged as a prominent cause of infectious morbidity and mortality globally. Posaconazole, a novel broad-spectrum triazole antifungal, is currently in clinical development and is undergoing FDA [...]

The continuing rise of resistance rates among bacteria today has led to the need for the development of new antibiotics with the ability to circumvent current resistance mechanisms. Daptomycin (Cubicin, [...]

It has been found that the management of a resident infected with methicillin-resistant Staphylococcus aure us (MRSA) is much more expensive for a long-term care facility (LTCF) than that of a methicillin-sensitive Staphylococcus aureus patient. A retrospective cohort study was carried out in a 37-bed LTCF that offers two levels of care.

Introduction: CARE was a Phase 3, randomized study evaluating the efficacy and safety of plazomicin-based combination therapy compared with colistin-based combination therapy for the treatment of patients with bloodstream infections or hospital-acquired/ventilator-associated pneumonia due to carbapenem-resistant Enterobacteriaceae (CRE). Adjunctive therapies included either tigecycline or meropenem. We sought to understand the contribution of tigecycline and meropenem to plazomicin-treated-patient outcomes by determining their observed pharmacodynamic exposures against baseline pathogens. Methods: Blood samples collected for plazomicin therapeutic monitoring were assayed for tigecycline and meropenem concentrations. Population pharmacokinetic models were constructed for each antibiotic. Using the individual Bayesian posterior or a covariate-based model, concentration time profiles were simulated to estimate the pharmacodynamic exposures for each patient. Pharmacodynamic thresholds for plazomicin, tigecycline, and meropenem were a total area under the curve to minimum inhibitory concentration ratio (AUC/MIC) ≥ 85, free (f) AUC/MIC ≥ 0.9, and free time above the MIC (fT > MIC) of ≥ 40%, respectively. Results: Fifteen plazomicin-treated patients were included (12 received tigecycline, 4 received meropenem, 1 received both). Microbiological response was observed in 13 (86.7%) and clinical efficacy was achieved in 11 (73.3%). Plazomicin achieved its pharmacodynamic target in all 15 patients. Meropenem fT > MIC was 0% in all 4 patients, and tigecycline fAUC/MIC was ≥ 0.9 in 9 (75%) patients. Overall, 6 (40%) of 15 patients had a tigecycline or meropenem exposure below the requisite thresholds. Microbiological response and clinical efficacy were observed in 100% (6/6) and 83.3% (5/6) of patients with low threshold attainment by tigecycline and meropenem dosing regimens, respectively. Conclusions: Plazomicin successfully achieved its requisite pharmacodynamic exposure, and these data suggest that optimization of tigecycline and meropenem therapy was not required for the combination to achieve microbiological response and clinical efficacy against serious CRE infections. Trial Registration: ClinicalTrials.gov number, NCT01970371. Funding: Achaogen, Inc.

The rise in Multidrug-resistant (MDR) infections has become a significant problem in both the developing countries and in the United States (U.S.). Specifically, MDR gram-negative infections are emerging, affecting not only adults but children as well. The specific gram-negative organisms that have been most concerning within the pediatric population include MDR P. aeruginosa, Enterobacteriaceae, and Acinetobacter spp. The increase in antimicrobial resistance rates is associated with various mechanisms with one of the most common being the production of beta-lactamases. Both Ceftazidime/Avibactam (CZA) and Ceftolozane/Tazobactam (C/T) are two recently approved antibiotics in the U.S. While both of these agents are inhibitors of beta-lactamase enzymes, there are differences between them that are important to understand. At this time, the data in children for these agents are extremely limited. The aim of this review is to describe the characteristics of these agents and their potential uses in pediatric patients.

ABSTRACTIntroduction: Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii.Areas covered: The authors summarize in vitroand in vivoefficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included.Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein.

ABSTRACTIntroduction: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP.Areas covered: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed.Expert opinion: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated.

ABSTRACTThe effectiveness of antimicrobial binding resins present in blood culture (BC) bottles in removing meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam is unknown. We assessed the time to detection (TTD) and growth of 2 Pseudomonas aeruginosaisolates in the presence of clinically meaningful concentrations of these antibiotics. Bactec Plus Aerobic/F and BacT/Alert FA Plus BC bottles were inoculated with one of two isolates (1 meropenem susceptible and 1 resistant), followed by fresh whole blood containing the peak, midpoint, or trough plasma concentrations for meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam. Matching bottles were loaded into their respective detection instruments and a standard incubator at 37°C, with TTD and CFU being monitored for up to 72 h. Bacterial growth was observed for 11/48 (22.9%), 22/48 (45.8%), and 47/48 (97.9%) of all BC bottles inoculated with the peak, midpoint, and trough concentrations, respectively (P= 0.001). When P. aeruginosawas isolated, the TTD was typically <26 h, and no differences between Bactec and BacT/Alert bottles were observed. In both systems, meropenem was removed to a greater degree than were ceftolozane and ceftazidime; however, concentrations for all antibiotics remained above the MIC for the susceptible organisms at 12 h. BC bottles containing antibiotic binding resins may not sufficiently inactivate achievable concentrations of meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam. The consistent identification of both P. aeruginosaisolates was observed only in the presence of antibiotic trough concentrations. To minimize false-negative BC results for patients already receiving these antibiotics, cultures should be collected just prior to the next dose, when antibiotic concentrations are lowest.

ABSTRACTIntroduction: Antimicrobial resistance is a serious health threat worldwide. Better understanding of exposure targets that could suppress resistance amplification is necessary to guide the dosing of currently available agents as well as new therapies in the drug development process.Areas covered: This review will discuss studies that focused on predicting development of resistance using the pharmacokinetic-pharmacodynamic approach and how to design dosing regimens that can successfully suppress resistance emergence in Gram-negative bacteria.Expert opinion: Pharmacokinetic-pharmacodynamic targets could provide useful insights to guide antimicrobial dosing to prevent resistance emergence. Exposure targets required for resistance suppression are higher than those for efficacy and might not be clinically feasible. Combination therapy is a possible approach to improve the efficacy and minimize the resistance emergence for difficult-to-treat infections.

Gram-negative multi-drug resistance is an emerging threat among pediatric patients with cystic fibrosis (CF). Ceftolozane/tazobactam (C/T) is an extended-spectrum cephalosporin/beta-lactamase inhibitor combination that has been shown to maintain activity against MDR P. aeruginosaisolates. The understanding of C/T effectiveness in pediatric patients is extremely limited. Minimum inhibitory concentration (MIC) testing and time-kill analyses were performed to better understand the antimicrobial susceptibility and potential role of C/T. Non-duplicate clinical respiratory MDR P. aeruginosaisolates (n= 5) from four pediatric CF patients were identified. MICs were determined for these isolates using CLSI broth microdilution methods. Time-kill analyses were performed using multiples of C/T alone, and combinations of C/T 2× and 8× the MIC with 30 mg/L tobramycin or 80 mg/L amikacin for all isolates. Cell counts were determined by serial dilution plating. Isolates had variable susceptibilities to C/T (range 0.5–8 mg/L), tobramycin (range 2 to >64 mg/L) and amikacin (range 8 to >256 mg/L). Time-kill analyses revealed an average of 0.71 (range −0.6 to 4.4), 1.50 (range 0.8–2.0) and 2.1 (range 1.2–3.4) log-kill at 4×, 8× and 16× the C/T MIC, respectively. At a tobramycin MIC of 32 mg/L, combination therapy showed synergistic benefit when the isolate was C/T susceptible. C/T and amikacin combination therapy showed synergistic activity at an amikacin MIC >256 mg/L when C/T MIC was 2 mg/L (4.7 log-kill at 2× C/T MIC and 4.0 log-kill at 8× C/T MIC). C/T appears to be a promising treatment option for treatment of MDR P. aeruginosain pediatric CF patients, both alone and in combination with tobramycin or amikacin. Interestingly, the benefit of C/T combination therapy with amikacin may be more pronounced than with the addition of tobramycin. Further evaluation of such combination regimens in pediatric CF patients is warranted.

Background: Pediatric pneumonia is one of the most common causes of childhood infection requiring hospitalization and is a substantial driver of antimicrobial use among hospitalized children. About 12-20% of pediatric patients hospitalized with community-acquired pneumonia (CAP) require critical care. Additionally, nosocomial pneumonias (i.e. hospital-acquired and ventilator- associated pneumonias) are responsible for 15-53% of hospital-associated infections and are the most common indication for empiric antibiotics in the pediatric intensive care unit. Objective: Respiratory infections, especially pneumonias, are a strong area for antimicrobial stewardship program (ASP) interventions, as they have been shown to improve patient outcomes while reducing inappropriate antimicrobial use, antimicrobial resistance, and overall costs. Method: Optimizing the selection of appropriate antimicrobial therapies is difficult for pediatric pneumonias because of the ill-defined definitive diagnostic criteria and difficulty differentiating between viral and bacterial etiology. Result: The aim of this review is to highlight the role of antimicrobial stewardship efforts in the treatment of pneumonias in critically ill children by discussing the emerging role of diagnostic criteria, the etiology of disease, appropriate targeted antimicrobial selection, and the optimization of antibiotic dosing and pharmacodynamic targets.

ABSTRACTObjectives: Skin and soft tissue infections (SSTIs) are among the most common bacterial diseases and represent a significant disease burden. The purpose of this study was to describe the real-world management of patients with SSTIs presenting to the emergency department (ED).Methods: This is a retrospective cohort study. Adult patients identified with a primary diagnosis of SSTI determined by ICD-9 codes were assessed from index presentation for up to 30 days. Records were reviewed 30 days prior to inclusion to ensure index hospitalization was captured. For recurrent visits, a similar strategy was implemented 30 days afterward.Results: Of 446 encounters screened, 357 were included; 106 (29.7%) were admitted to the hospital and 251 (70.3%) were treated outpatient. Of patients with a Charlson Comorbidity Index (CCI) score two or greater, 60.9% were treated as inpatients, whereas admission rates were 30.1% and 14.1% for patients with a CCI score of one and zero, respectively. Inpatients had an average length of stay (LOS) of 7.3 ± 7.1 days. No difference was detected in overall re-presentation to the facility 22.6% and 28.3% (p > 0.05) or in SSTI related re-presentation 10.4% and 15.1% (p > 0.05) between inpatient and outpatients. The most common gram-positive organisms identified on wound/abscess culture were MSSA (37.1% inpatients) and MRSA (66.7% outpatients). Mean total cost of care was $13,313 for inpatients and $413 for outpatients.Conclusion: This analysis identifies opportunities to improve processes of care for SSTIs with the aim of decreasing LOS, reducing readmissions, and ultimately decreasing burden on the healthcare system.

ABSTRACTCeftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r= 0.71, P< 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 μg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosaAPE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.)

ABSTRACTThis article was written with the aim to establish a consensus clinical pathway for long-acting lipoglycopeptide antibiotics such as oritavancin (Orbactiv®) and dalbavancin (Dalvance®) for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Seven infectious diseases pharmacy specialists from a variety of facilities across the United States (US) participated in a roundtable discussion to consider the use of newer single-dose long-acting lipoglycopeptides, and integrate them into clinical pathways for ABSSSI. They identified two ways of treating with these drugs: first, to facilitate discharge from the hospital by switching from initial therapy (e.g., with intravenous (IV) vancomycin) and second, to avoid hospital admission altogether, since the product can be administered in several outpatient settings of care including the emergency department (ED), observation unit (OU) or outpatient infusion center. The participants used existing literature on classification and treatment of ABSSSI and their experience in the clinical setting as bases for their discussion and came to a consensus on the considerations for patient inclusion and exclusion as well as a pathway for outpatient treatment with long-acting lipoglycopeptides. As a result of the discussion, we concluded that the current treatment paradigm for ABSSSI is ripe for re-evaluation and reconfiguration in order to more closely align with the changing healthcare landscape. Hospital stakeholders are constantly searching for new strategies that can improve quality of care while simultaneously reducing overall expenses. The availability of single-dose long-acting lipoglycopeptides is an opportunity to opt for lower-cost outpatient treatment of appropriate ABSSSI patients. This article proposes the inclusion and exclusion considerations, along with a consensus treatment pathway, that could provide a solid foundation for facilities to construct and adapt their own effective clinical pathways for ABSSSI.

ABSTRACTWe describe a pediatric cystic fibrosis patient who developed a pulmonary exacerbation due to two multidrug-resistant (MDR) Pseudomonas aeruginosaisolates. In addition to these MDR organisms, the case was further complicated by β-lactam allergy. Despite the MDR phenotype, both isolates were susceptible to an antimicrobial combination.

SUMMARYBeta-lactam antibiotics serve as a cornerstone in the management of bacterial infections because of their wide spectrum of activity and low toxicity. Since resistance rates among bacteria are continuously on the rise and the pipeline for new antibiotics does not meet this trend, an optimization of current beta-lactam treatment is needed. This review provides an overview of optimization through use of prolonged- and continuous-infusion dosing strategies compared with more traditional intermittent infusions. Included is an overview of the scientific basis for using these nontraditional prolonged- and continuous-infusion-based regimens, with a focus on major areas in which the clinical laboratory can support the clinical use of these regimens.

ABSTRACTWe assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.

ABSTRACTMembers of the tetracycline class are frequently classified as bacteriostatic. However, recent findings have demonstrated an improved antibacterial killing profile, often achieving ≥3 log10bacterial count reduction, when such antibiotics have been given for periods longer than 24 h. We aimed to study this effect with eravacycline, a novel fluorocycline, given in an immunocompetent murine thigh infection model over 72 h against two methicillin-resistant Staphylococcus aureus(MRSA) isolates (eravacycline MICs = 0.03 and 0.25 μg/ml) and three Enterobacteriaceaeisolates (eravacycline MICs = 0.125 to 0.25 μg/ml). A humanized eravacycline regimen, 2.5 mg/kg of body weight given intravenously (i.v.) every 12 h (q12h), demonstrated progressively enhanced activity over the 72-h study period. A cumulative dose response in which bacterial density was reduced by more than 3 log10CFU at 72 h was noted over the study period in the two Gram-positive isolates, and eravacycline performed similarly to comparator antibiotics (tigecycline, linezolid, and vancomycin). A cumulative dose response with eravacycline and comparators (tigecycline and meropenem) over the study period was also observed in the Gram-negative isolates, although more variability in bacterial killing was observed for all antibacterial agents. Overall, a bacterial count reduction of ≥3 log was achieved in one of the three isolates with both eravacycline and tigecycline, while meropenem achieved a similar endpoint against two of the three isolates. Bactericidal activity is typically defined in vitroover 24 h; however, extended regimen studies in vivomay demonstrate an improved correlation with clinical outcomes by better identification of antimicrobial effects.

OBJECTIVEHospitalized influenza patients are often treated with antibiotics empirically while awaiting final diagnosis. The goal of this study was to describe the inappropriate continuation of antibiotics for influenza respiratory tract infections (RTIs).DESIGNWe retrospectively studied adults admitted to our institution over 2 respiratory flu seasons with positive influenza RTIs. Inappropriate antibiotic duration (IAD) was defined as antibiotic use for >24 hours after a positive influenza test in patients presenting with <72 hours of RTI symptoms and with no other indications of bacterial infection.RESULTSDuring the study period, 322 patients included in this study were admitted for influenza RTI. Respiratory cultures were ordered for 50 of these patients (15.5%) and 71 patients (22%) had a positive chest x-ray, but antibiotics were prescribed to 211 patients (65.5%) on admission. Antibiotics were inappropriately continued in 73 patients (34.5%). Patients receiving IAD had a longer length of stay (LOS) (median, 6 days; range, 4–9 days) compared with those whose antibiotics were discontinued appropriately (median, 5 days; range, 3–8 days) and those who were not treated with antibiotics (median, 4 days; range, 3–6 days; P<.001). However, mortality was similar among these 3 groups: 3 patients (4.1%) from the IAD cohort died; 6 patients (4.3%) from the group with an appropriate antibiotic duration died; and 2 patients [1.8%] from the group given no antibiotics died (P=.510). The 30-day readmission rates were similar as well: 9 patients (12.3%) from the IAD group were readmitted within 30 days; 21 patients (15.2%) from the group with appropriate antibiotic duration were readmitted; and 11 patients (9.9%) from the group given no antibiotics were readmitted (P=.455). Total hospital costs were greater in patients treated with IAD ($10,645; range, $6,485–$18,035) compared with the group treated with appropriate antibiotic duration ($7,479; range, $4,866–$12,922) and the group given no antibiotics $5,961 (range, $4,711–$9,575). Thus, the hospital experienced a median loss in net hospital revenue of $2,076 per IAD patient compared with a patient for which antibiotic duration was appropriate.CONCLUSIONThe majority of patients with influenza RTI received antibiotics on admission, and 34.5% were inappropriately continued on antibiotics without evidence of bacterial infection, which led to increased LOS, loss of net revenue, and no improvement in outcome. Thus, stewardship initiatives aimed at this population are warranted.Infect Control Hosp Epidemiol2016;37:583–589

Ceftolozane/tazobactam (C/T) is a novel antibiotic approved for complicated intra-abdominal and urinary tract infections caused by Gram-positive and Gram-negative organisms, including some MDR strains. Little is known about the use of this agent for treatment of bacteremia and even less so about the appropriateness of the renally defined regimens. We describe a case of a 66-year-old man with a history of chronic kidney disease (baseline Cr = 3–4 mg/dl) and recurrent nephrolithiasis with bilateral stents who had positive concurrent urine and blood cultures for MDR Pseudomonas aeruginosa(PSA), susceptible only to amikacin and colistin. Due to the MDR phenotype and his underlying kidney disease, the 375 mg (250 mg/125 mg) dose of C/T was given as monotherapy every 8 h for his bloodstream infection. Once steady state was anticipated, blood was obtained at the end of infusion (1 h), and at 3, 5 and 8 h for drug concentration determination using a validated high-performance liquid chromatography method at the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford. The minimum inhibitory concentration (MIC) for the PSA was 2/4 for C/T, indicating susceptibility. Concentration of ceftolozane of 21.87 µg/ml at 8 h indicated that serum concentrations were maintained above the MIC throughout the dosing interval. The patient was given 25 days of C/T and experienced a successful clinical outcome. Blood cultures obtained at 1 and 3 weeks after completion of treatment remained sterile. No adverse events were attributed to C/T. In this patient, the renally adjusted dose of C/T was safe and provided sufficiently high drug concentrations that exceeded the MIC of the infecting organism over the course of therapy. More data are required to determine the clinical utility of C/T in the setting of MDR PSA bacteremia.

ABSTRACTIntroduction: Antimicrobial resistance is a potentially inevitable consequence of widespread use of antibiotics in the healthcare system. An enhanced understanding of pharmacodynamic (PD) targets that prevent antimicrobial resistance development will improve currently availably therapies and help to guide future drug development strategies. Current in vitromethods to predict bacterial resistance to antimicrobials consist of serial dilution experiments, determination of the mutant prevention concentration (MPC), mutant selection window (MSW), and human simulated pharmacodynamics studies. Clinical trial data and real -world surveillance studies can help validate or disprove in vitromodeling.Areas covered: This review will discuss methods of predicting development of resistance and how the use of pharmacodynamics can reduce or eliminate the emergence of resistance among Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcusspecies.Expert opinion: Pharmacodynamic targets can be used successfully to guide antimicrobial therapy to prevent resistance development. Currently, PD targets do not take into consideration horizontal resistance gene transfer and various factors may lead to different PD targets based on sites of infection. Further research is necessary to guide future drug development strategies and optimize new drug therapies.

ABSTRACTThe percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds for fT>MICwere identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [n= 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD]) fT>MICthan those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%], P< 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%], P< 0.001). CART identified fT>MICthreshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those with fT>MICof >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7; P= 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepime fT>MICresulted in a 2% improvement in multivariate survival probability (P= 0.015). Achieving a cefepime fT>MICof 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued.

In patients with first episode Clostridium difficileinfection treated with vancomycin or fidaxomicin, more patients receiving fidaxomicin achieved at least 2 log10colony-forming units/g reduction in spores at the follow-up visit (P=.02). Similar to published literature, a higher proportion of patients receiving fidaxomicin demonstrated sustained clinical response.Infect. Control Hosp. Epidemiol.2016;37(2):215–218

While the Clinical and Laboratory Standards Institute (CLSI) recommends against routine screening for extended spectrum β-lactamases (ESBLs), knowledge of these data can provide valuable insights regarding epidemiology and drug therapy decisions. The purpose of this study was to compare the impact of minimum inhibitory concentration (MIC)-based screening versus phenotypic confirmatory testing of ESBLs on the susceptibility profile of selected antimicrobials. Broth microdilution MICs were determined for various antimicrobial agents against a collection contemporary clinical Escherichia coliand Klebsiella pneumoniaeisolates. Isolates identified as ESBL-positive by MIC screening were then subjected to confirmatory phenotypic testing. Percent susceptibility was based on CLSI or United States Food and Drug Administration breakpoints. Four-hundred and forty-two (18%) isolates screened positive for ESBL production. Of these, 274 (62%) were confirmed positive for ESBL production; 28 (10%) were also carbapenem non-susceptible. We found an under-prediction of activity for ceftolozane/tazobactam (C/T), ertapenem (ETP), meropenem (MEM), and piperacillin/tazobactam (TZP) when considering only the screen-positive testing. For agents with potential activity against ESBLs such as C/T, TZP, ETP, and MEM, reduced susceptibility was noted when only considering the MIC screen-positive test. Although phenotypic screening selects for resistant organisms, inclusion of other genotypes besides ESBL (i.e., AmpC, carbapenemase) may falsely under-predict the potency against some ESBL producers and may limit applicability of surveillance data to geographic areas not plagued with carbapenemase producers. Cubist Pharmaceuticals.

ABSTRACTVancomycin is considered a first-line antibiotic for complicated skin and skin structure infections (cSSSI) because of the risk of methicillin-resistant Staphylococcus aureus(MRSA). The vancomycin exposure of tissue can vary widely in patients with cSSSI, yet most models test only the average exposure. The in vitropharmacodynamic model was used to simulate three tissue exposure levels attained by administering vancomycin at 1 g every 12 h (q12h), based on the median (50th), 25th, and 10th percentile tissue area under the concentration-time curve (AUC) values observed during an in vivomicrodialysis study of diabetic patients. Four clinical isolates (two of MRSA [vancomycin MIC, 1 and 2 μg/ml] and two of methicillin-susceptible S. aureus[MSSA] [MIC, 1 and 2 μg/ml]) were evaluated. Experiments were performed over 72 h in duplicate. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) during the final 24-h dosing interval (48 to 72 h) (AUBC48–72) was calculated. Reductions in the 72-h number of CFU/ml and AUBC48–72at the different exposure levels were compared. Target tissue vancomycin exposure levels for the 50th (AUC0–12, 102.0 ± 9.1 μg · h/ml), 25th (AUC0–12, 44.3 ± 1.8 μg · h/ml), and 10th (AUC0–12, 25.3 ± 3.1 μg · h/ml) percentiles were obtained in all studies. No differences in the 72-h number of CFU or AUBC were observed between exposure levels when all of the isolates were analyzed together. However, for the two MRSA isolates, the 10th percentile exposure level achieved a lower 72-h number of CFU/ml (−1.4 ± 0.4 log10CFU/ml, P= 0.007) and a greater AUBC48–72(97.1 ± 20.0 log10CFU · h/ml, P= 0.011) than the higher exposure levels. The majority of the tissue exposure levels achieved with a vancomycin dosing regimen of 1 g q12h resulted in substantial killing of MSSA and MRSA; however, the lowest exposure levels observed in a minority of the population may explain the poor vancomycin response.

Although many antimicrobial agents display good in vitro activity against the pathogens frequently implicated in diabetic foot infections, effective treatment can be complicated by reduced tissue penetration in this population secondary to peripheral arterial disease and emerging antimicrobial resistance, which can result in clinical failure. Improved characterization of antibiotic tissue pharmacokinetics and penetration ratios in diabetic foot infections is needed. Microdialysis offers advantages over the skin blister and tissue homogenate studies historically used to define antibiotic penetration in skin and soft-tissue infections by defining antibiotic penetration into the interstitial fluid over the entire concentration versus time profile. However, only a select number of agents currently recommended for treating diabetic foot infections have been evaluated using these methods, which are described herein. Better characterization of the tissue penetration of antibiotic agents is needed for the development of methods for maximizing the pharmacodynamic profile of these agents to ultimately improve treatment outcomes for patients with diabetic foot infections.

ABSTRACTTelavancin is a lipoglycopeptide with potent activity against methicillin-resistant Staphylococcus aureus(MRSA) and methicillin-susceptible S. aureus(MSSA). The activity of telavancin against MRSA and MSSA after prior vancomycin exposure was studied in an in vitropharmacodynamic model. Two clinical MRSA and two MSSA isolates, all with vancomycin MICs of 2 μg/ml, were subjected to humanized free drug exposures of vancomycin at 1 g every 12 h (q12h) for 96 h, telavancin at 750 mg q24h for 96 h, and vancomycin at 1 g q12h for 72 h followed by telavancin at 750 mg q24h for 48 h (120 h total). The microbiological responses were measured by changes from 0 h in log10CFU/ml at the end of experiments and area under the bacterial killing and regrowth curves over 96 h (AUBC0−96). The control isolates grew to 8.8 ± 0.3 log10CFU/ml. Initially, all regimens caused −4.5 ± 0.9 reductions in log10CFU/ml by 48 h followed by slight regrowth over the following 48 to 72 h. After 96 h, vancomycin and telavancin achieved −3.7 ± 0.9 and −3.8 ± 0.8 log10CFU/ml changes from baseline, respectively (P= 0.74). Sequential exposure to telavancin after vancomycin did not result in additional CFU reductions or increases, with ultimate log10CFU/ml reductions of −4.3 ± 1.1 at 96 h and −4.2 ± 1.3 at 120 h (P> 0.05 for all comparisons at 96 h). The AUBC0–96was significantly smaller for the regimen of telavancin for 96 h than for the regimens of vancomycin for 96 h and vancomycin followed by telavancin (P≤ 0.04). No resistance was observed throughout the experiment. Against these MRSA and MSSA isolates with vancomycin MICs of 2 μg/ml, telavancin was comparable with vancomycin and its activity was unaffected by prior vancomycin exposure.

ABSTRACTRespiratory infection with Burkholderia cenocepaciais associated with accelerated decline in lung function and increased mortality in cystic fibrosis (CF) patients (A. M. Jones, M. E. Dodd, J. R. W. Govan, V. Barcus, C. J. Doherty, J. Morris, and A. K. Webb, Thorax 59:948–951, 2004, http://dx.doi.org/10.1136/thx.2003.017210). B. cenocepaciaoften possesses innate resistance to multiple antimicrobial classes, making eradication uncommon in established infection (P. B. Davis, Am J Respir Crit Care Med 173:475–482, 2006, http://dx.doi.org/10.1164/rccm.200505-840OE). We report the use of clinafloxacin in a CF patient with advanced B. cenocepaciainfection, present pharmacokinetic (PK) data, and discuss the potential therapeutic role of clinafloxacin in patients with this condition.

Urinary tract infection (UTI) is one of the most prevalent admission diagnoses in hospital-based clinical practice. Despite its frequency, few data are available regarding its demographics and economic implications.

ABSTRACTThe objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosaby using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivomodel, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosaisolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R2= 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosaisolate JJ 4-36, as the in vivoresponses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivofailures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosadue to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivotesting is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivodisconnect in P. aeruginosa.

Background: Vancomycin is a common treatment option for skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus(MRSA). Given the increasing prevalence of MRSA, vancomycin is widely used as empirical therapy. In patients with lower-limb infections, antimicrobial penetration is often reduced because of decreased vascular perfusion. In this study, we evaluated the tissue concentrations of vancomycin in hospitalized patients with lower-limb infections.Methods: An in vivo microdialysis catheter was inserted near the margin of the wound and was perfused with lactated Ringer's solution. Tissue and serum samples were obtained after steady state for one dosing interval. Tissue concentrations were corrected for percentage of in vivo recovery using the retrodialysis technique.Results: Nine patients were enrolled (mean ± SD: age, 54 ± 19 years; weight, 105.6 ± 31.5 kg). Patients received a mean of 12.8 mg/kg of vancomycin every 12 hours (n 7), every 8 hours (n 1), or every 24 hours (n 1). Mean ± SD steady-state trough vancomycin concentrations in serum and tissue were 11.1 ± 3.3 and 6.0 ± 2.6 μg/mL. The mean ± SD 24-hour free drug areas under the curve for serum and wound were 283.7 ± 89.4 and 232.8 ± 75.7 μgh/mL, respectively. The mean ± SD tissue penetration ratio was 0.8 ± 0.2.Conclusions: These data suggest that against MRSA with minimum inhibitory concentrations of 1 μg/mL or less, vancomycin achieved blood pharmacodynamic targets required for the likelihood of success. Reduced concentrations may contribute to poor outcomes and the development of resistance. As other literature suggests, alternative agents may be needed when the pathogen of interest has a minimum inhibitory concentration greater than 1 μg/mL.

Introduction:Complicated intra-abdominal infections and urinary tract infections are frequently associated with Gram-negative bacteria and treatment can be hampered by the involvement of resistant organisms. A common resistance mechanism is β-lactamase production which confers resistance to β-lactam antibiotics.Areas covered:This article summarizes β-lactamases found among Gram-negative bacteria as well as providing an overview of complicated intra-abdominal infections and urinary tract infections and the impact inappropriate antibiotic therapy and antibiotic resistance has in their treatment. The author reviews the activity of ceftazidime-avibactam, including animal model data and microbiological data from Phase II clinical trials. This article also highlights Phase III clinical trials of ceftazidime-avibactam that are ongoing or completed and briefly discusses other β-lactamase inhibitor combinations currently in development.Expert opinion:The increasing problem and complexity of β-lactamase resistance has been met by resurgence in the development of β-lactamase inhibitor combinations. These show promise in the treatment of resistant infections. One β-lactamase inhibitor in advanced development with a broad spectrum of activity is avibactam, covering class A, class C and some class D enzymes. Importantly, the activity of avibactam also includes carbapenemases such as the KPC and OXA-48. The combination of avibactam with the cephalosporin ceftazidime is attractive, given the spectrum of antimicrobial activity and the low toxicity of the cephalosporin class.

ABSTRACTGSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitroactivity against key causative respiratory pathogens, including methicillin-resistant Staphylococcus aureus(MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log10CFU at 24 h compared with 0 h controls and the area under the concentration-time curve for the free, unbound fraction of a drug (fAUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log10CFU in neutropenic mice. The mean fAUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 ± 34.6 and 148.4 ± 83.3, respectively. GSK2140944 displayed in vitroand in vivoactivity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA.

ABSTRACTThe combination of cefepime with AAI101, a novel extended-spectrum β-lactamase inhibitor, possesses potent in vitroactivity against many resistant Gram-negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime-nonsusceptible strains of the family Enterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and the in vivoefficacy of simulated human doses of cefepime and cefepime-AAI101 in a neutropenic murine thigh infection model. At 2 h after inoculation, mice were dosed with regimens that provided a profile mimicking the free drug concentration-time profile observed in humans given cefepime at 2 g every 8 h (q8h; as a 30-min infusion) or cefepime-AAI101 at 2 g/0.5 g q8h (as a 30-min infusion). Efficacy was determined by calculation of the change in thigh bacterial density (log10number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 ± 0.1 log10CFU (mean ± standard error) was observed in control animals. Efficacy for cefepime monotherapy was observed against only 3 isolates, whereas increases in bacterial density similar to that in the control animals were noted for the remaining 17 strains (all with cefepime MICs of ≥64 mg/liter). The humanized cefepime-AAI101 dosing regimen resulted in bacterial reductions of ≥0.5 log10CFU for 12 of the 20 strains. Evaluation of efficacy as a function of the fraction of the dosing interval during which free drug concentrations were above the MIC determined with different fixed concentrations of AAI101 suggested that a fixed concentration of 8 mg/liter AAI101 is most predictive of in vivoactivity for the studied regimen.

ABSTRACTPreliminary enthusiasm over the encouraging spectrum and in vitroactivities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivoefficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosaand provide evidence that efflux inhibition may circumvent this in vivo-relevant resistance liability.