In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral ß-lactam/ß-lactamase inhibitor combination.

OBJECTIVES: Oral ß-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable ß-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model. METHODS: Twelve ceftibuten-resistant clinical isolates (six Klebsiella pneumoniae, five Escherichia coli and one Enterobacter cloacae) were utilized. Ceftibuten/ledaborbactam MICs ranged from 0.12 to 2 mg/L (ledaborbactam fixed at 4 mg/L). A ceftibuten murine dosing regimen mimicking ceftibuten 600 mg q12h human exposure was developed and administered alone and in combination with escalating exposures of ledaborbactam. The log10 cfu/thigh change at 24 h relative to 0 h controls was plotted against ledaborbactam fAUC0-24/MIC and the Hill equation was used to determine exposures associated with bacteriostasis. RESULTS: The mean ±â€ŠSD 0 h bacterial burden was 5.96 ±â€Š0.24 log10 cfu/thigh. Robust growth (3.12 ±â€Š0.93 log10 cfu/thigh) was achieved in untreated control mice. Growth of 2.51 ±â€Š1.09 log10 cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure-response relationships were strong (mean ±â€ŠSD R2 = 0.82 ±â€Š0.15). The median ledaborbactam fAUC0-24/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model. CONCLUSIONS: Ledaborbactam fAUC0-24/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against ß-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145).

Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa.

The in vitro activity of WCK 5222 (cefepime-zidebactam) was compared to that of several available combination therapies among 30 clinical carbapenem-resistant Pseudomonas aeruginosa (CRP) strains using gradient diffusion strips. The combinations included nonsusceptible ß-lactams (cefepime, ceftolozane-tazobactam, and meropenem) with amikacin and fosfomycin. WCK 5222 MICs ranged from 2 to 32 mg/liter, and 97% were ≤16 mg/liter, while 105/146 (72%) combinations demonstrated inhibition below established susceptibility breakpoints. WCK 5222 monotherapy may be preferred over the combinations assessed for CRP infections.

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

BACKGROUND: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. METHODS: Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a ß-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. RESULTS: Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L. CONCLUSIONS: For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

In Vivo Efficacy of Humanized WCK 5222 (Cefepime-Zidebactam) Exposures against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Thigh Model.

Herein, we describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against carbapenem-resistant Acinetobacter baumannii strains in a neutropenic murine thigh infection model. Five of the six isolates examined expressed OXA-23 or OXA-24. WCK 5222, despite showing MICs of 16 to 64 mg/liter, produced remarkable in vivo activity; human-simulated exposure showed a decline in the bacterial burden for all isolates (mean reduction, -2.09 ± 1.01 log10 CFU/thigh), while a lack of activity was observed with cefepime and zidebactam monotherapies.

Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Murine Lung Infection Model.

We evaluated the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) against cefepime-resistant Acinetobacter baumannii strains (n = 13) in the neutropenic murine lung infection model. Twelve isolates were meropenem resistant. In control animals and those that received cefepime or zidebactam alone, the mean bacterial growth at 24 h was >2 log10 CFU/lung compared with 0-h controls (6.32 ± 0.33 log10 CFU/lung). WCK 5222 produced a decline in the bacterial burden for all isolates (mean reduction, -3.34 ± 0.85 log10 CFU/lung) and demonstrated remarkable potency.

Characterization of Potentially Unsafe Ambulatory Antibiotic Use and Associated Outcomes in an Adult Kidney Transplant Population.

BACKGROUND: Antibiotics are frequently prescribed to kidney transplant (KTX) recipients in the outpatient setting, but there are limited data assessing the safety and outcomes associated with this practice. OBJECTIVE: The primary objective of this study was to describe ambulatory antibiotic prescribing in a large cohort of adult KTX recipients. The secondary objective was to assess the outcomes associated with potentially unsafe antibiotic use in this population. METHODS: National Veterans Health Administration data compiled between 2001 and 2010 were used to conduct a pharmacovigilance assessment of antibiotic prescribing, excluding intravenous agents, antifungals, antivirals, and prophylactic regimens. Multivariable Cox proportional hazard regression was used to determine the impact of safe and potentially unsafe antibiotic use on time to event for graft loss. RESULTS: Among 5130 KTX recipients and 30 127 patient-years of follow-up, 14 259 antibiotic courses were prescribed at a rate of 0.47 courses per patient-year. Transplant or nephrology providers prescribed 24.8% of courses. Overall, 608 courses (4.3%) in 311 patients (6.1%) were considered potentially unsafe for dosages in disagreement with recommended adjustments for renal function, interaction with immunosuppressive regimens, and other pertinent safety concerns. After adjusting for baseline characteristics, unsafe antibiotic use was associated with a 40% higher risk of graft loss (adjusted hazard ratio = 1.40; 95% CI = 1.03-1.89; P = 0.030) compared with safe use. CONCLUSIONS AND RELEVANCE: Although unsafe antibiotic prescribing was uncommon, it was associated with increased risk of graft loss. Prospective research is needed to elucidate whether the driver of poor outcomes is the safety of the antibiotic prescription or fragmented care.

Evaluation of the in vitro activity of WCK 5222 (cefepime/zidebactam) and currently available combination therapies against single- and double-carbapenemase producing Enterobacteriaceae: Expanding the zone of hope.

Cefepime/zidebactam (WCK 5222) is a ß-lactam/ß-lactam enhancer antibiotic designed to retain in vitro activity against Enterobacteriaceae that simultaneously produce metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL). Aztreonam (ATM) plus ceftazidime/avibactam (CZA) or meropenem/vaborbactam (M/V) is an attractive option for coverage of such strains, but clinical laboratories are not equipped to distinguish which is the more potent regimen to inform treatment decisions. We evaluated Enterobacteriaceae that expressed MBL and ≥1 SBL (n=15) using gradient diffusion strip (GDS) methods to (1) determine the minimum inhibitory concentration (MIC) of WCK 5222 and (2) compare the in vitro potency of CZA+ATM vs. M/V+ATM. All isolates were non-susceptible to ATM, CZA, and M/V and were inhibited by WCK 5222 at cefepime concentrations ≥2 log2 dilutions below the susceptible-dose dependent breakpoint of 8 mg/L (MIC50/90, 1/2 mg/L). Activity of CZA+ATM vs. M/V+ATM was compared using the zone of hope (ZOH) product, quantitated by multiplying the length (in mm) of inhibited growth adjacent to each GDS from the point of intersection. The median (interquartile range) ZOH product for CZA+ATM and M/V+ATM was 75.4 (62.8-93.7) and 23.5 (14.1-60.4), respectively (P=0.002). In strains with one carbapenemase (the MBL), the median ZOH products were not statistically different, but in strains with an OXA-type carbapenemase (n=6), the median product for CZA+ATM and M/V+ATM was 78.1 and 20.7, respectively (P=0.004). Thus, CZA+ATM may offer enhanced coverage over M/V+ATM of Enterobacteriaceae co-expressing MBL and SBL. Further preclinical in vivo evaluations of WCK 5222 monotherapy are warranted.

Prevalence of in vitro synergistic antibiotic interaction between fosfomycin and nonsusceptible antimicrobials in carbapenem-resistant Pseudomonas aeruginosa.

PURPOSE: We assessed the synergistic potential of fosfomycin and parenteral antibiotics among carbapenem-resistant Pseudomonas aeruginosa (CRP). METHODOLOGY: Minimum inhibitory concentrations (MICs) were determined by broth microdilution for all antibiotics except fosfomycin, for which the gradient diffusion strip (GDS) method was used. The GDS cross method was performed to assess interactions between fosfomycin and: aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam and tobramycin. Only organisms that were nonsusceptible to the second drug were assessed. RESULTS: Among 153 clinical isolates, the fosfomycin MIC50/90 was 48/≥1024 mg l-1 . Synergy was detected in 131/604 (21.7 %) fosfomycin-antibiotic combinations among 76 (49.7 %) isolates. Ceftazidime (42/81, 51.9%) and ceftolozane/tazobactam (7/14, 50.0%) displayed synergy most frequently. Meropenem susceptibility was restored in 21 (13.7 %) isolates. Antagonism was not observed. CONCLUSION: Fosfomycin synergy was commonly observed in vitro among CRP. These data may guide the selection of combination antibiotic therapy. The susceptibility to other antibiotics was restored in combination with fosfomycin, warranting further in vivo evaluation.

In vitro investigation of synergy among fosfomycin and parenteral antimicrobials against carbapenemase-producing Enterobacteriaceae.

Intravenous fosfomycin is undergoing clinical development in the United States for treatment of complicated urinary tract infections (cUTIs) and may be prescribed as a component of dual antibiotic regimens against carbapenemase-producing Enterobacteriaceae (CPE). Fosfomycin, aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam, and tobramycin minimum inhibitory concentrations (MICs) were determined by gradient diffusion strip (GDS) against CPE isolates (N = 49). The GDS cross method was used to assess antibiotic interactions between fosfomycin and the aforementioned parenteral antibiotics. The resultant fractional inhibitory concentration index was used to classify interactions. Fosfomycin-containing combinations were evaluated only if nonsusceptible to the second agent. The fosfomycin MIC50 was ≥1024 mg/L by GDS. Synergy or additivity was detected in 80 (22%) fosfomycin-containing combinations. Antagonism was not observed. Ceftolozane/tazobactam most frequently displayed synergy [8 (16.3%) isolates]. When CPE are isolated, clinical laboratories should consider performing GDS synergy tests to identify favorable antibiotic interactions.

Assessment of the Physical Compatibility of Eravacycline and Common Parenteral Drugs During Simulated Y-site Administration.

PURPOSE: Eravacycline is a broad-spectrum, intravenous fluorocycline antibiotic approved for the treatment of complicated intra-abdominal infections in adults. A 60-minute infusion is recommended for each infused dose. Compatibility data that may allow convenient Y-site administration of eravacycline with other parenteral medications are unavailable. We aimed to determine the physical compatibility of eravacycline with other intravenous medications by simulated Y-site administration. METHODS: Eravacycline was reconstituted according to published prescribing information and diluted with 0.9% sodium chloride to a concentration of 0.6 mg/mL. Simulated Y-site administration was performed by mixing 5 mL of eravacycline with an equal volume of 51 other intravenous medications, including crystalloid and carbohydrate hydration fluids and 20 antimicrobials. Secondary medications were assessed at the upper range of concentrations considered standard for intravenous infusion. Mixtures underwent visual inspection and turbidity measurement immediately on mixture and at 3 subsequent time points (30, 60, and 120 minutes after admixture), and pH was measured at 60 minutes for comparison with the baseline value of the secondary medication. FINDINGS: Eravacycline was physically compatible with 41 parenteral drugs (80%) by simulated Y-site administration. Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, colistimethate sodium, furosemide, meropenem, meropenem/vaborbactam, micafungin sodium, propofol, and sodium bicarbonate. IMPLICATIONS: Eravacycline for injection was physically compatible with most parenteral medications assessed. Pharmacists and nurses should be knowledgeable of the observed incompatibilities with eravacycline to prevent the unintentional mixing of incompatible intravenous medications.

Impact of a co-curricular, e-learning activity on pharmacy student knowledge of laboratory values.

BACKGROUND AND PURPOSE: Pharmacists are increasingly taking on roles that require interpretation of laboratory values. We sought to assess the impact of a co-curricular, e-learning activity on pharmacy student knowledge of laboratory values. EDUCATIONAL ACTIVITY AND SETTING: We implemented a co-curricular, e-learning activity during the 2015-2016 academic year at the South Carolina College of Pharmacy. While students in all professional years could participate, the activity was required for those in their third professional year (P3). The activity consisted of a two-hour recorded lesson and accompanying handout. We administered a pre-assessment consisting of 10 multiple-choice questions, followed by a post-assessment comprised of 20 questions, including the 10 questions from the pre-assessment. Mean scores on these 10 questions were compared before and after the activity. FINDINGS: Two hundred and thirty-five students completed the activity. Mean pre-assessment scores numerically increased as year of study increased; ranging from 65.0% to 93.4%. Compared to mean pre-assessment scores for all students, mean post-assessment scores were higher (82.2% vs. 94.3%, p < 0.001). When pre- and post-assessment scores were evaluated by year of study, significant improvements in post-assessment scores were observed for all groups (p ≤ 0.009). SUMMARY: Following the completion of a co-curricular, e-learning activity designed to provide instruction on laboratory values for pharmacy students, increases in mean post-assessment scores were observed. Applicability of our results is reduced for students outside of the P3 year.

Where should antibiotic gradient diffusion strips be crossed to assess synergy? A comparison of the standard method with a novel method using steady-state antimicrobial concentrations.

Multi-drug resistance among Pseudomonas aeruginosa in hospitals, and particularly intensive care units, has achieved alarming rates. Some combination antimicrobial therapies have demonstrated promising synergistic effects and an ability to overcome resistance without increasing drug-related toxicities. Nevertheless, rapid and feasible methods to identify synergy have not been routinely implemented in clinical microbiology laboratories. Synergistic activity of meropenem plus tobramycin or levofloxacin against clinical P. aeruginosa isolates (N=21) was assessed by two different methods using gradient diffusion strips (GDSs). A 90° angle was created at the intersection of the minimum inhibitory concentration (MIC) of each drug by the standard method, and by a novel method, the cross was placed at clinically relevant steady-state concentrations (Css) based on recommended dosing regimens. Fractional inhibitory concentration indexes were determined to describe antibiotic interactions. Time-kill analyses were performed over 24 h in duplicate for instances of discordance between the standard cross method and the novel method. Synergy between meropenem and tobramycin by the novel method was observed in one (4.8%) isolate and between meropenem and levofloxacin in two (9.5%) isolates. Agreement with the standard method was 86-100% for meropenem plus tobramycin and meropenem plus levofloxacin combinations, respectively. Time-kill studies resulted in agreement with GDSs crossed at Css in two of three instances of discordance between GDS methods. This novel method of synergy testing that involves crossing GDSs at steady-state concentrations may be a rapid and feasible tool for routine practice. Further comparisons of this novel procedure with time-kill methods are needed.

Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia.

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold. Data were pooled from seven published trials assessing outcomes in daptomycin-treated enterococcal bacteraemia, including patients receiving daptomycin (≥72 h) and any ß-lactam, intravenous aminoglycoside, linezolid, tigecycline and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding and daptomycin Etest MIC. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following pooling of data, 240 adults were included; 137 (57.1%) were alive at 30 days. A majority of patients were immunosuppressed (65.8%) and received a ß-lactam (94.6%). Examining the threshold in low-acuity patients (n = 135) to control for co-morbidities, these patients were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% vs. 20.0%; P = 0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (P = 0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤ 2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteraemia.

Assessing the in vitro activity of ceftazidime/avibactam and aztreonam among carbapenemase-producing Enterobacteriaceae: Defining the zone of hope.

Ceftazidime/avibactam plus aztreonam (CZA+ATM) is an emerging option to combat carbapenemase-producing Enterobacteriaceae (CPE) expressing resistance via multiple ß-lactamases within Ambler classes A, B, C, and D. The benefit of this combination is apparent when the pathogen-specific resistance genotype is characterized. However, rapid molecular diagnostic systems may be unavailable to allow this precision medicine-based approach. Using synergy tests with antibiotic gradient diffusion strips (GDSs), we aimed to prove that the defined phenotypic profile of CPE is reliably predicted by the genotype to confirm the utility of this method as a phenotypic profiling tool for use in the clinical setting. Synergy assessments for CPE (n=10) that co-produce serine- and metallo-ß-lactamases were performed by crossing CZA and ATM antibiotic GDSs (Liofilchem® and Etest®). The minimum inhibitory concentration (MIC):MIC ratio method was also conducted for five CPE. All CPE were resistant to CZA and ATM when tested alone. Using classical fractional inhibitory concentration definitions, synergy (9/10) and additivity (1/10) was detected by at least one method for all isolates. As predicted by cross-coverage of genotypically defined serine- and metallo-ß-lactamases, for all isolates CZA+ATM produced a phenotypic profile distinguished by sizeable zones of inhibited growth which we term the 'zone of hope'. In conclusion, simple procedures utilizing antibiotic GDSs were concordant with the known genotypic profile of the CPE selected for study. This approach appears to be a valuable tool for guiding therapy in the absence of molecular diagnostic systems. Furthermore, this study confirms potent in vitro activity of CZA+ATM against CPE expressing multiple ß-lactamases.

Investigational drugs for the treatment of infections caused by multidrug-resistant Gram-negative bacteria.

INTRODUCTION: 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 vitro and in vivo efficacy 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.

Physical Compatibility of Meropenem and Vaborbactam With Select Intravenous Drugs During Simulated Y-site Administration.

PURPOSE: Meropenem/vaborbactam is a novel intravenous antibiotic combining the carbapenem, meropenem, with a novel ß-lactamase inhibitor, vaborbactam. Meropenem/vaborbactam is administered as a 3-hour infusion given every 8 hours, thereby potentially restricting an intravenous line for 9 h/d. Intravenous medications may be given concurrently via Y-site when compatibility data are available. Herein, physical compatibility was determined for the identification which medications can be coadministered with meropenem/vaborbactam via Y-site. METHODS: Y-site administration was simulated in vitro by admixing 5 mL of meropenem 8 mg/mL and vaborbactam 8 mg/mL with an equal volume of 88 other diluted intravenous medications, including 34 antimicrobials. All other medications were diluted with 0.9% sodium chloride to the upper range of concentrations considered standard for intravenous infusion. Visual inspection, turbidity measurement, and pH measurement were performed prior to admixture, directly after admixture, and at time points up to 3 hours after admixture. FINDINGS: Of the 88 medications tested, meropenem/vaborbactam was compatible with 73 (83%), including many antibiotics such as aminoglycosides (amikacin, gentamicin, and tobramycin), colistin, fosfomycin, linezolid, tedizolid, tigecycline, and vancomycin. Physical incompatibility was observed with albumin, amiodarone, anidulafungin, calcium chloride, caspofungin, ceftaroline, ciprofloxacin, daptomycin, diphenhydramine, dobutamine, isavuconazole, midazolam, nicardipine, ondansetron, and phenytoin. IMPLICATIONS: The majority of intravenous medications tested were found to be physically compatible with meropenem/vaborbactam. These data will help pharmacists and nurses to improve line access in patients receiving meropenem/vaborbactam.

Physical compatibility of plazomicin with select i.v. drugs during simulated Y-site administration.

PURPOSE: The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported. METHODS: Plazomicin injection solution (500 mg/10 mL) was diluted in 0.9% sodium chloride or 5% dextrose for injection to a final volume of 50 mL (final plazomicin concentration, 24 mg/mL), consistent with a 15-mg/kg dose administered to an 80-kg patient (i.e., 1,200 mg). All other i.v. drugs were reconstituted according to manufacturers' recommendations and diluted with 0.9% sodium chloride or 5% dextrose for injection to the upper range of concentrations used clinically. Y-site conditions were simulated by mixing 5 mL of plazomicin solution with 5 mL of tested drug solutions in a 1:1 ratio. Solutions were assessed for visual (via color and Tyndall beam testing), turbidity (using a laboratory-grade turbidimeter), and pH changes over a 60-minute observation period. Incompatibility was defined a priori as precipitation, color change, a positive Tyndall test, or a turbidity change of ≥0.5 nephelometric turbidity units at any time during the 60-minute observation period. RESULTS: Plazomicin was physically compatible with 79 of the 92 drugs tested. Determinations of physical incompatibility with plazomicin were made for 13 drugs: albumin, amiodarone, amphotericin B deoxycholate, anidulafungin, calcium chloride, daptomycin, esomeprazole, heparin, levofloxacin, methylprednisolone, micafungin, phenytoin, and propofol, CONCLUSION: Plazomicin at a concentration of 24 mg/mL was physically compatible with 85% of the drugs tested, including 31 of 36 antimicrobial agents.

Bipolar depression: Managing patients with second generation antipsychotics.

Bipolar affective disorder is a debilitating illness that manifests as cyclical episodes of mood elevation and depression, but the treatment of the depressive episodes (i.e., bipolar depression) differs considerably from the treatment of major depressive disorder. In bipolar affective disorder, it is well known that patients spend a significantly greater amount of time in depressive episodes than manic or hypomanic episodes, yet there are currently just three Food and Drug Administration-approved agents for the treatment of bipolar depression: (1) olanzapine/fluoxetine combination (2) quetiapine, both immediate- and extended-release, and (3) lurasidone. The literature review presented here focuses on the clinical trials that led to the Food and Drug Administration-approval of these second generation antipsychotics in the treatment of bipolar depression. The discussion highlights key considerations regarding overall treatment strategies to aid clinicians in the selection of pharmacologic agents. Recommended monitoring parameters, potential adverse effects, and pertinent counseling points for second generation antipsychotics used in bipolar depression are included.