A Tapered-pulsed Fidaxomicin Regimen Following Treatment in Patients With Multiple Clostridioides difficile Infection Recurrences.

We treated 46 patients with multiple recurrent Clostridioides difficile infections (mrCDI) using a tapered-pulsed (T-P) fidaxomicin regimen, the majority of whom failed prior T-P vancomycin treatment. Sustained clinical response rates at 30 and 90 days were 74% (34/46) and 61% (28/46). T-P fidaxomicin shows promise for management of mrCDI.

Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects.

A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects (n = 32) received a single, weight-stratified, fixed dose of 500 mg (n = 4), 750 mg (n = 8), or 1,000 mg (n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC0-∞) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC0-∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.).

Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants.

The pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n = 11) and urine (n = 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 µg/ml, time to Cmax (Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0-24) = 151.6 ± 35.6 versus 156.6 ± 42.5 µg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 µg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%; P < 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.).

Inhaled Antibiotics for Gram-Negative Respiratory Infections.

Gram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects, in vitro and microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration.

Ceftazidime-avibactam administered at 1.25 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Prefiltration plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 h along with postfiltration and ultrafiltrate concentrations at h 2 and h 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were as follows: maximum plasma concentration (Cmax), 61.10 and 14.54 mg/liter; minimum plasma concentration (Cmin), 31.96 and 8.45 mg/liter; half-life (t1/2), 6.07 and 6.78 h; apparent volume of distribution at the steady state (Vss), 27.23 and 30.81 liters; total clearance at the steady state (CLss), 2.87 and 2.95 liters/h; area under the concentration-time curve from 0 to 8 h (AUC0-8), 347.87 and 85.69 mg · h/liter. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/liter) throughout the 8-h dosing interval. Mean CVVH extraction ratios for ceftazidime and avibactam were 14.44% and 11.53%, respectively, and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 liters/h and for avibactam was 1.59 liters/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data that include multiple patients and dialysis modes are needed to verify the optimal ceftazidime-avibactam dosing strategy during critical illness and CVVH.

Compatibility of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, and Piperacillin-Tazobactam with Vancomycin in Dextrose 5% in Water.

Objectives: The compatibility of vancomycin with existing and novel ß-lactam/ß-lactamase inhibitors at clinically relevant concentrations in 5% dextrose in water has not been fully explored to date. Methods: Vancomycin concentrations tested ranged from 5 to 20 mg/mL. Ceftazidime-avibactam was tested at 8, 20, and 40 mg/mL, ceftolozane-tazobactam at 15 mg/mL, and piperacillin-tazobactam at 28 mg/mL. Compatibility of drug admixtures were tested via both simulated and actual y-site infusion. For the simulated y-site compatibility assessment, 1:1 mixtures of each respective drug were analyzed over 24 hours. Actual y-site infusion followed a 4-hour extended-infusion protocol, with aliquots tested hourly for 4 hours. At all time points, the compatibility of each admixture was determined using 6 different methods: visual, microscopic, Tyndall beam, nephelometric, pH, and microbiologic bioassay assessment. If any admixture failed any one of these 6 assays, it was considered incompatible. Any combination deemed incompatible was filtered through a 0.22 µm filter and reanalyzed to assess impact of particle size. Results: There were no differences in compatibility categorizations between simulated and actual y-site infusion. There were no changes in compatibility over the time course of any experiment. Ceftazidime-avibactam at 8 mg/mL was incompatible with vancomycin at 5 mg/mL. The maximum compatible vancomycin concentrations were 5 mg/mL and 10 mg/mL with 20 and 40 mg/mL of ceftazidime-avibactam, respectively. Ceftolozane-tazobactam 15 mg/mL was compatible with vancomycin concentrations up to 10 mg/mL. The maximum compatible vancomycin concentration with piperacillin-tazobactam 28 mg/mL was 5 mg/mL. None of the ß-lactam/ß-lactamase inhibitors tested were compatible with 15 or 20 mg/mL of vancomycin. None of the admixtures considered incompatible by other methods displayed any decrease in antimicrobial activity as assessed by bioassay. After filtration, all admixtures originally deemed incompatible maintained their visual turbidity and microscopic particulate matter. Conclusions: Ceftazidime-avibactam prepared at the lowest concentration recommended in the package insert is incompatible with vancomycin. Ceftolozane-tazobactam did not display incompatibility until vancomycin concentrations above 10 mg/mL were tested. Piperacillin-tazobactam at a typical extended-infusion concentration is compatible with vancomycin in D5W. To our knowledge, this is the first study to assess compatibility of antibiotic admixtures via direct measurement of antimicrobial activity. The lack of any decrement in antibacterial activity of any apparently incompatible admixture and maintenance of incompatibility after passage through a 0.22 µm filter may suggest a lack of clinically relevant adverse effects when co-administered. Future compatibility studies should incorporate appropriate methods to accurately assess both efficacy and safety of co-administered drug products.

Microbiological Assessment of Polymyxin B Components Tested Alone and in Combination.

We investigated the antimicrobial activity of four polymyxin B components, B1, B2, B3, and isoleucine (Ile)-B1, individually and in combination. B3 was the most active agent against all organisms tested except Acinetobacter baumannii, for which Ile-B1 was most active. One combination met the criteria for synergy, B3 plus Ile-B1. No combinations exhibited antagonism. The dominant components of polymyxin B products (B1 and B2) were associated with the lowest probability of improved antibacterial activity when combined.

Pharmacokinetics of ceftaroline in normal body weight and obese (classes I, II, and III) healthy adult subjects.

The pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m(2) and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m(2) compared to those <30 kg/m(2). A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 µg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.).

Management and Outcomes of Patients at a Specialty Clinic for Clostridioides difficile Infection.

Vancomycin and fidaxomicin taper regimens were the most common treatment strategies employed but nearly half of patients (40/83) referred to our Clostridioides difficile infection (CDI) clinic did not require further treatment. The overall 60-day CDI recurrence rate was 16.9% (11/65). CDI management at a dedicated clinic may improve clinical outcomes.

Polymyxins: wisdom does not always come with age.

We currently face a lack of new antimicrobial therapies in an era of increasingly common multidrug-resistant (MDR) bacteria. The polymyxins have become last-line treatments for patients with MDR bacterial infections. An increasing body of published literature has attempted to answer questions about dosing, pharmacology, and susceptibility testing of these drugs, yet each takes for granted purity and potency of the 2 available polymyxin products. In the case of polymyxin B, true potency may vary by as much as 40% from the content reported in prescribing information. This poor accuracy is related to quality assurance assays established in the 1940s and currently in use, which have been shown to be significantly flawed in recent investigations. This review discusses the limitations of pharmacological knowledge about polymyxin antimicrobials, the clinical impact of these limitations, and suggestions for further study of these drugs in order to optimize their use clinically.

A national evaluation of antibiotic expenditures by healthcare setting in the United States, 2009.

OBJECTIVES: Promoting appropriate antibiotic use has the potential to decrease healthcare costs by reducing unnecessary prescriptions and the incidence of resistant infections. However, little is known about where antibiotic costs are incurred in the US healthcare system. We evaluated antibiotic expenditures by healthcare setting and antibiotic class in the USA. METHODS: Systemic antibiotic expenditures in 2009 were extracted from the IMS Health(©) National Sales Perspectives database. These data represent a statistically valid projection of all medication purchases in the USA from 1 January 2009 to 31 December 2009. RESULTS: Antibiotic expenditures totalled $10.7 billion. The majority (61.5%) of expenditures were associated with the outpatient setting, especially from community pharmacies. Inpatient and long-term care settings accounted for 33.6% and 4.9% of expenditures, respectively. The class of antibiotics that accounted for the most antibiotic expenditure overall was the quinolones, followed by the penicillins. CONCLUSIONS: Over $10.7 billion was spent in 2009 on antibiotic therapy in the USA. Differences were observed in antibiotic expenditures by healthcare setting, with the majority in the outpatient setting, 87% of which was in community pharmacies.

Behind closed doors: medication storage and disposal in the home.

BACKGROUND: More than half of all medications are inappropriately prescribed, dispensed, or sold and only 50% of patients take their medications correctly. Oftentimes, unwanted or expired medications are saved for later use, stored indefinitely, or disposed via the sink, toilet, or garbage. OBJECTIVE: To determine how residents in Cook County, Illinois, use, store, and dispose of their medications to assess the possible impact of these medications on health care and the environment. METHODS: Researchers at the University of Illinois conducted a survey of Cook County residents over a 13-week period. Residents were surveyed regarding their use, storage, and disposal of prescription and nonprescription medications. RESULTS: From 3954 telephone numbers generated through random-digit dialing, 445 telephone interviews were completed. Eighty-one and a half percent of respondents had prescription medications and 92.4% had nonprescription medications in their homes. On average, respondents possessed 4.4 distinct prescription and 5.5 distinct nonprescription medications. Despite possessing a number of medications, approximately 30% of respondents stated that they took no medication on a regular basis; 59% of respondents reported disposing medications in the household gar bage and 31% flushed them down the toilet or sink. Over 80% of respondents stated that they had never received information about proper medication disposal. Thirty-seven percent reported having leftover unexpired medications from a previous illness. Of these, 63% stopped taking their medications because they believed that they no longer needed them or because they felt better. Thirty-two percent of respondents expected to have leftover prescription medications within the next 6 months. CONCLUSIONS: Almost all respondents had excess and leftover medications in their homes. This may be a result of both overprescribing and poor medication adherence. In addition to the potential human health risk of nonadherence, disposal of excess medication raises concerns about their environmental impact and safety.

Commonly Reported Mosquito-Borne Viruses in the United States: A Primer for Pharmacists.

Mosquito-borne diseases are a public health concern. Pharmacists are often a patient's first stop for health information and may be asked questions regarding transmission, symptoms, and treatment of mosquito borne viruses (MBVs). The objective of this paper is to review transmission, geographic location, symptoms, diagnosis and treatment of MBVs. We discuss the following viruses with cases in the US in recent years: Dengue, West Nile, Chikungunya, LaCrosse Encephalitis, Eastern Equine Encephalitis Virus, and Zika. Prevention, including vaccines, and the impact of climate change are also discussed.

Pharmacokinetic evaluation of cefiderocol for the treatment of multidrug resistant Gram-negative infections.

INTRODUCTION: Cefiderocol is a siderophore cephalosporin antibiotic and first of its kind approved by the Food and Drug Administration for the treatment of complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years or older caused by susceptible organisms. Cefiderocol's unique mechanism of iron chelation improves Gram-negative membrane penetration as the bacteria's iron uptake mechanism recognizes the chelated iron antibiotic and iron for entry. This also allows for the evasion of cefiderocol from cell entry-related resistance mechanisms. AREAS COVERED: This review covers the mechanism of action, resistance mechanisms, pharmacokinetics in various patient populations, and pharmacodynamics. Relevant literature evaluating efficacy and safety are discussed. EXPERT OPINION: Limited treatment options are available for the treatment of carbapenem-resistantorganisms. Clinical trials have demonstrated that cefiderocol is no worse than alternative treatment options for cUTIs and HABP/VABP, but more data are currently available to support the use of beta-lactam beta-lactamase inhibitor agents, where susceptible. Mortality differences demonstrated in patients with pneumonia and bloodstream infections must further be explored and logistical and practical considerations regarding susceptibility testing and use as monotherapy vs. combination therapy must be considered prior to confidently recommending cefiderocol for regular use in systemic infections.

Efficacy of oritavancin alone and in combination against vancomycin-susceptible and -resistant enterococci in an in-vivo Galleria mellonella survival model.

OBJECTIVE: The optimal therapy for serious enterococcal infections, especially vancomycin-resistant enterococci (VRE), remains unclear, although combination therapy is often recommended. Oritavancin has demonstrated in-vitro activity against VRE, but data evaluating oritavancin in combination with other agents and in in-vivo systems are lacking. The objective of this study was to evaluate the efficacy of oritavancin alone and in combination with ceftriaxone, daptomycin, gentamicin, linezolid and rifampin against vancomycin-susceptible enterococci and VRE in an in-vivo Galleria mellonella survival model. METHODS: Five enterococcal strains were used: three clinical isolates (VRE S38141, VRE H19570, VRE W21579), Enterococcus faecium ATCC 700221 and Enterococcus faecalis ATCC 29212. G. mellonella larvae were inoculated with the test strain followed by the test drug at humanized weight-based dose alone or in combination within 1 h of inoculation. After injection, larvae were incubated at 37°C and survival was measured daily for 7 days. Survival was plotted using the Kaplan-Meier method, and differences between groups were determined via the log-rank test. Mean survival times were also determined. RESULTS: Each single agent improved survival significantly compared with the untreated control strain. Oritavancin was the most efficacious single agent, and led to a significant increase in survival compared with ceftriaxone, gentamicin and daptomycin. Compared with oritavancin alone, none of the oritavancin combinations tested were significantly better, and mean survival times were comparable. CONCLUSIONS: Oritavancin monotherapy had the highest survival rate at 7 days, and none of the combinations tested showed improved survival over oritavancin alone. These data add to the body of literature rebutting the routine use of combination therapy with oritavancin for the treatment of infections due to VRE.