Publications by authors named "Thomas P Lodise"

156 Publications

US-Focused Conceptual Health Care Decision-Analytic Models Examining the Value of Pivmecillinam Relative to Current Standard-of-Care Agents Among Adult Patients With Uncomplicated Urinary Tract Infections due to Enterobacterales.

Open Forum Infect Dis 2021 Oct 15;8(10):ofab380. Epub 2021 Oct 15.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.

Background: Pivmecillinam is approved for the treatment of adults with uncomplicated urinary tract infection (uUTI) in Canada and Europe and is pending United States (US) Food and Drug Administration submission for consideration for approval. US-focused health care decision-analytics were developed to define the value of an agent like pivmecillinam relative to current standard-of-care (SOC) agents among adult patients with Enterobacterales uUTIs based on its improved microbiologic activity against common Enterobacterales.

Methods: The model population was 100 theoretical adult outpatients with Enterobacterales uUTIs under 4 different uUTI first-line empiric treatment scenarios (ie, pivmecillinam, nitrofurantoin, trimethoprim-sulfamethoxazole [SXT], or fluoroquinolones). The total mean uUTI-related 30-day costs, including inappropriate treatment costs, were calculated for each regimen. The range of pivmecillinam regimen costs that conferred cost savings relative to the current SOC agents based on its potentially improved microbiologic activity against common Enterobacterales was determined.

Results: The 30-day uUTI-related costs associated with nitrofurantoin, SXT, and fluoroquinolones were $655.61, $687.57, and $659.69, respectively. The pivmecillinam neutral regimen cost thresholds that resulted in the same uUTI-related 30-day per-patient costs for nitrofurantoin, SXT, and fluoroquinolones were $83.50, $115.45, and $87.58, respectively. The overall antimicrobial susceptibility improvement required with pivmecillinam fixed at $200/regimen, for it to be cost savings relative to SOC agents, was 28%.

Conclusions: The analyses suggests that an agent like pivmecillinam, if approved in the US, has the potential to reduce the economic burden associated with inappropriate treatment of adult outpatients with uUTIs, especially in patients at high risk for an Enterobacterales uUTI that is resistant to SOC agents.
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http://dx.doi.org/10.1093/ofid/ofab380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516593PMC
October 2021

Use of oral tetracyclines in the treatment of adult outpatients with skin and skin structure infections: Focus on doxycycline, minocycline, and omadacycline.

Pharmacotherapy 2021 Sep 24. Epub 2021 Sep 24.

Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.

Oral tetracyclines have been used in clinical practice for over 60 years. One of the most common indications for use of oral tetracyclines is for treatment of adult outpatients with skin and soft infections (SSTIs), including acute bacterial skin and skin structure infections (ABSSSIs). The 2014 Infectious Diseases Society of America (IDSA) skin and soft tissue guideline strongly recommends sulfamethoxazole/trimethoprim, clindamycin, and tetracyclines as oral treatment options for patients with purulent SSTIs, especially when methicillin-resistant Staphylococcus aureus is of clinical concern. Despite the long-standing use of tetracyclines, practice patterns indicate that they are often considered after other guideline-concordant oral options for the treatment of patients with SSTIs. Clinicians may therefore be less familiar with the clinical data associated with use of commercially available tetracycline agents for treatment of patients with SSTI. This review summarizes the literature on the use of oral tetracyclines (ie, doxycycline, minocycline, and omadacycline) for the treatment of adult patients with SSTIs. As part of this review, we describe their common mechanisms of resistance, susceptibility profiles against common SSTI pathogens, pharmacokinetics and pharmacodynamics, and comparative clinical data.
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http://dx.doi.org/10.1002/phar.2625DOI Listing
September 2021

Of Rats and Men: a Translational Model To Understand Vancomycin Pharmacokinetic/Toxicodynamic Relationships.

Antimicrob Agents Chemother 2021 09 2;65(10):e0106021. Epub 2021 Aug 2.

Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Vancomycin area under the concentration curve (AUC) is known to predict vancomycin-induced acute kidney injury (AKI). Data were analyzed from a rat model ( = 48) and two prospective clinical studies (PROVIDE [ = 263] and CAMERA2 [ = 291]). A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and in the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg·h/liter, respectively.
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http://dx.doi.org/10.1128/AAC.01060-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448150PMC
September 2021

Treatment of patients with serious infections due to carbapenem-resistant Acinetobacter baumannii: How viable are the current options?

Pharmacotherapy 2021 Sep 22;41(9):762-780. Epub 2021 Jul 22.

Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.

This review critically appraises the published microbiologic and clinical data on the treatment of patients with carbapenem-resistant Acinetobacter baumannii infections. Despite being recognized as an urgent threat pathogen by the CDC and WHO, optimal treatment of patients with serious CRAB infections remains ill-defined. Few commercially available agents exhibit reliable in vitro activity against CRAB. Historically, polymyxins have been the most active agents in vitro, though interpretations of susceptibility data are difficult given issues surrounding MIC testing methodologies and lack of correlation between MICs and clinical outcomes. Most available preclinical and clinical data involve use of polymyxins, tetracyclines, and sulbactam, alone and in combination. As the number of viable treatment options is limited, combination therapy with a polymyxin is often used for patients with CRAB infections, despite the significant risk of nephrotoxicity. However, no treatment regimen has been found to reduce mortality, which exceeds 40% across most studies, or substantially improve clinical response. While some newer agents, such as eravacycline and cefiderocol, have demonstrated in vitro activity, clinical efficacy has not been fully established. New agents with clinically relevant activity against CRAB isolates and favorable toxicity profiles are sorely needed.
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http://dx.doi.org/10.1002/phar.2607DOI Listing
September 2021

Outcomes of adult patients in the intensive care unit with Pseudomonas aeruginosa pneumonia who received an active anti-pseudomonal β-lactam: Does "S" equal success in the presence of resistance to other anti-pseudomonal β-lactams?

Pharmacotherapy 2021 08 5;41(8):658-667. Epub 2021 Jul 5.

Kaiser Permanente Southern California Department of Research & Evaluation, Pasadena, California, USA.

Study Objectives: The most commonly prescribed antibiotics for patients with hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) due to Pseudomonas aeruginosa are the conventional anti-pseudomonal β-lactams (APBLs) (ie, ceftazidime, cefepime, meropenem, or piperacillin-tazobactam). Similar resistance mechanisms in P. aeruginosa affect the APBLs, and it is unclear if resistance to one APBL can affect the effectiveness of other APBLs. This exploratory, hypothesis-generating analysis evaluates the impact of APBL resistance among patients in the intensive care unit (ICU) with P. aeruginosa HABP/VABP who initially receive a microbiologically active APBL.

Design: A retrospective cohort [GJ1] [LT2] study.

Setting: Kaiser Permanente Southern California members (01/01/2011-12/31/2017).

Patients: The study included adult patients admitted to the ICU with a monomicrobial P. aeruginosa HABP/VABP who received a microbiologically active APBL within 2 days of index P. aeruginosa respiratory culture.

Intervention: Patients were stratified by presence of resistance to APBL on index P. aeruginosa (0 vs. ≥1 resistant APBL).

Measurements: Primary outcomes were 30-day mortality and discharge to home.

Main Results: Overall, 553 patients were included. Thirty-day mortality was 28%, and 32% of patients were discharged home. Eighty-eight patients (16%) had a P. aeruginosa HABP/VABP that was resistant to ≥1 APBL (other than active empiric treatment). Relative to patients with no APBL resistance, patients with resistance to ≥1 APBL had a higher 30-day mortality (adjusted odds ratio (aOR) [95% confidence interval (CI)]: 1.65 [1.02-2.66]) and were less likely to be discharged home (adjusted hazard ratio (aHR) [95% CI]: 0.50 [0.29-0.85]).

Conclusion: Further study is needed, but this exploratory analysis suggests that the full APBL susceptibility profile should be considered when selecting therapy for patients with P. aeruginosa HABP/VABP.
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http://dx.doi.org/10.1002/phar.2600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457199PMC
August 2021

Hospital admission patterns of adult patients with complicated urinary tract infections who present to the hospital by disease acuity and comorbid conditions: How many admissions are potentially avoidable?

Am J Infect Control 2021 May 30. Epub 2021 May 30.

Spero Therapeutics, Cambridge, MA.

Background: Hospital admissions for complicated urinary tract infections (cUTI) in the United States are increasing but there are limited information on the acuity of patients who are admitted.

Objective: Describe hospitalization patterns among adult cUTI patients who present to the hospital with cUTI and to determine the proportion of admissions that were of low acuity.

Methods: A retrospective multi-center analysis using data from the Premier Healthcare Database (2013-2018) was performed.

Inclusion Criteria: age ≥ 18 years, cUTI diagnosis, positive blood or urine culture. Hospital admissions were stratified by presence of sepsis, systemic symptoms but no sepsis, and Charlson Comorbidity Index (CCI).

Results: 187,789 patients met the inclusion criteria. The mean (SD) age was 59.7 (21.9), 40.4% were male, 29.4% had sepsis, 16.7% had at least 1 systemic symptom (but no sepsis), and 53.9% had no sepsis or systemic symptoms. The median [inter-quartile range] CCI was 1 [0, 3]. Sixty-four percent of patients were admitted to hospital, and 18.9% of admissions occurred in patients with low acuity (no sepsis or systemic symptoms and a CCI ≤ 2). The median [IQR] LOS and costs for low acuity inpatients who were admitted were 3 [2, 5] days and $5,575 [$3,607, $9,133], respectively.

Conclusion: Nearly 1 in 5 cUTI hospital admissions occurred in patients with low acuity, and therefore may be avoidable.
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http://dx.doi.org/10.1016/j.ajic.2021.05.013DOI Listing
May 2021

Response to the Letter to the Editor Regarding "Intraclass Difference in Pneumonia Risk with Fluticasone and Budesonide in COPD: A Systematic Review of Evidence from Direct-Comparison Studies" [Response to Letter].

Int J Chron Obstruct Pulmon Dis 2021 10;16:1227-1229. Epub 2021 May 10.

Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA.

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http://dx.doi.org/10.2147/COPD.S315195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121281PMC
July 2021

The case for precision dosing: medical conservatism does not justify inaction.

J Antimicrob Chemother 2021 06;76(7):1661-1665

Children's Hospital Los Angeles and University of Southern California, Los Angeles, CA, USA.

The need for precision dosing has been challenged on the basis of insufficient evidence. Herein, we argue that adequate evidence exists to conduct therapeutic drug monitoring (TDM) and precisely target antibiotic exposures. While achievement of any antibiotic concentration does not guarantee efficacy sans toxicity for any single patient, stochastic control optimizes the probability of achieving favourable responses across patients. We argue that variability in targets (such as the organism's MIC) can be considered with models. That is, complexity alone does not relegate the decision-making framework to 'clinician intuition'. We acknowledge the exposure-response relationships are modified by patient-specific factors (other drugs, baseline organ functional status etc.) and describe how precision dosing can inform clinical decision making rather than protocolize it. Finally, we call for randomized, controlled trials; however, we suggest that these trials are not necessary to make TDM standard of care for multiple classes of antibiotics.
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http://dx.doi.org/10.1093/jac/dkab086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212772PMC
June 2021

Validity of 2020 vancomycin consensus recommendations and further guidance for practical application.

Am J Health Syst Pharm 2021 07;78(15):1364-1367

University of Arkansas for Medical Sciences College of Pharmacy & Arkansas Children's Hospital Little Rock, AR, USA.

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http://dx.doi.org/10.1093/ajhp/zxab123DOI Listing
July 2021

Vancomycin Area Under the Curve-Guided Dosing and Monitoring for Adult and Pediatric Patients With Suspected or Documented Serious Methicillin-Resistant Staphylococcus aureus Infections: Putting the Safety of Our Patients First.

Clin Infect Dis 2021 05;72(9):1497-1501

Institute for Therapeutic Innovation, University of Florida, Orlando, Florida, USA.

The revised vancomycin consensus guidelines recommended area under the curve (AUC)-guided dosing/monitoring for patients with serious invasive methicillin-resistant Staphylococcus aureus (MRSA) infections as a measure to minimize vancomycin-associated acute kidney injury (VA-AKI) while maintaining similar effectiveness. Data indicate that the intensity of vancomycin exposure drives VA-AKI risk. Troughs of 15-20 mg/L will ensure an AUC ≥400 mg × hr/L but most patients will have daily AUCs >600. VA-AKI increases as a function of AUC, especially when >600. In addition to minimizing VA-AKI risk while maintaining similar efficacy, AUC-guided dosing/monitoring is a more precise way to conduct therapeutic drug monitoring for vancomycin relative to trough-only control.
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http://dx.doi.org/10.1093/cid/ciaa1744DOI Listing
May 2021

Decision Analysis: Omadacycline Relative to Moxifloxacin Among Hospitalized Community-Acquired Bacterial Pneumonia Patients at Risk of Clostridioides difficile Infection.

Clin Drug Investig 2021 Mar 19;41(3):269-275. Epub 2021 Feb 19.

Paratek Pharmaceuticals, Inc., King of Prussia, PA, USA.

BACKGROUND AND OBJECTIVE: Omadacycline is an aminomethylcycline antibiotic approved in the USA as once-daily intravenous/oral monotherapy for adults with community-acquired bacterial pneumonia (CABP). Omadacycline demonstrated noninferiority to the fluoroquinolone moxifloxacin in a phase III CABP trial; adverse-event rates were similar between treatment groups except for Clostridioides difficile infection (CDI), which occurred in 2% of moxifloxacin-treated patients and 0% of patients on omadacycline. Conceptual healthcare-decision analytic models were developed to better understand the economic implications of antibiotic selection and CDI risk in acute-care facilities.

Methods: A conceptual healthcare-decision analytic model was created to estimate incremental costs associated with treating 100 hospitalized CABP patients with an initial 5-day inpatient regimen of omadacycline instead of moxifloxacin. The underlying model assumption was that treatment with omadacycline has the potential to reduce CDI events relative to moxifloxacin. The model included excess costs associated with each treatment group from admission through discharge. Attributable CDI cost per case in the moxifloxacin group varied from $15,000 to $45,000 (US$). Omadacycline acquisition cost was $300-600/day for 5 days.

Results: At a CDI attributable cost per case of $30,000 (base-case analyses), the incremental treatment cost (US$) per 100 patients ranged from $300,000 to $- 120,000 (cost savings). The excess CDI incidence in moxifloxacin-treated patients would need to be 5-10% for omadacycline to be cost-saving, assuming the attributable CDI cost is approximately $30,000.

Conclusion: Targeted omadacycline use may reduce economic burden associated with hospitalized CABP patients treated with moxifloxacin if it can reduce excess cases of moxifloxacin-associated CDI.
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http://dx.doi.org/10.1007/s40261-021-01005-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079290PMC
March 2021

Hospital Readmissions and Mortality Among Intubated and Mechanically Ventilated Adult Subjects With Pneumonia Due to Gram-Negative Bacteria.

Respir Care 2021 May 16;66(5):742-750. Epub 2021 Feb 16.

Xcenda, Palm Harbor, Florida.

Background: Ventilator-associated pneumonia (VAP) is one of the most common hospital-acquired infections in ICUs and is associated with significant morbidity and mortality. Gram-negative bacteria cause 55-85% of hospital-acquired pneumonia and are associated with increased mortality.

Methods: This study sought to describe mortality rates and 30-d readmission rates among intubated and mechanically ventilated subjects with Gram-negative pneumonia and to explore associated risk factors for mortality and rehospitalization using data from the 2013 Healthcare Cost and Utilization Project (HCUP) National Readmission Database. The study sample included adults age ≥ 18 y who were hospitalized with invasive, continuous mechanical ventilation; were discharged between February 1, 2013, and November 30, 2013; and had a primary or secondary diagnosis of Gram-negative bacterial pneumonia. Logistic regression was used to identify subject characteristics significantly associated with mortality and readmissions.

Results: Using the HCUP projected sample of 32,683 intubated and mechanically ventilated subjects with Gram-negative pneumonia, the mortality rate during the index hospitalization was 24.3%. More than one fifth of subjects (22.9%) who survived the index hospitalization were readmitted within 30 d of discharge. Among subjects with readmissions, 18% occurred within 3 d of discharge, 39% occurred within 7 d of discharge, and 65% occurred within 14 d of discharge. Subjects with prior hospitalization within 30 d of the index hospitalization had a higher risk of readmission with an odds ratio of 1.70 (95% CI 1.48-1.94).

Conclusions: Mortality was high and readmissions were substantial among intubated and mechanically ventilated subjects with Gram-negative pneumonia.
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http://dx.doi.org/10.4187/respcare.07754DOI Listing
May 2021

Comparative effectiveness of early-targeted use of fidaxomicin versus oral vancomycin among hospitalized veterans' affairs patients with infections due to Clostridioides difficile.

Pharmacotherapy 2021 02 8;41(2):212-219. Epub 2021 Feb 8.

Samuel S. Stratton Veteran's Affairs Medical Center, Albany, New York, USA.

Study Objectives: This study sought to compare real-world effectiveness outcomes between hospitalized patients with Clostridioides difficile infections (CDIs) who received early-targeted fidaxomicin or oral vancomycin at two Veterans Affairs Medical Centers (VAMCs).

Design: A retrospective cohort study was performed among hospitalized patients at two VAMCs from January 2008 until July 2017.

Setting: Albany and Syracuse VAMCs.

Patients: Patients were included in this analysis if they were age ≥18 years; were hospitalized; had a CDI with a Hines Severity Score Index (SSI) ≥2; received oral vancomycin (January 2008-June 2014 at Albany or Syracuse VAMCs) or fidaxomicin (March 2012-July 2017 at Albany VAMC) within 5 days of positive CDI stool sample for ≥ 48 hours.

Intervention: Receipt of an oral vancomycin- or fidaxomicin-containing CDI regimen.

Measurements: The primary outcome was a composite of 30-day mortality and 60-day recurrence.

Main Results: The study included 54 oral vancomycin and 38 fidaxomicin recipients. The population was predominantly male (97.8%), and mean ± standard deviation age was 74.6 ± 11.1 years. The composite outcome was significantly different between fidaxomicin and vancomycin recipients (26.3% fidaxomicin vs. 51.9% vancomycin; odds ratio (OR): 0.33, 95% CI: 0.14-0.81, p = 0.01). This finding was maintained in the multivariate analysis after adjustment for confounders (adjusted OR: 0.25, 95% CI: 0.09-0.73, p = 0.01) CONCLUSIONS: This real-world effectiveness study suggests that use of fidaxomicin potentially results in better outcomes relative to oral vancomycin for initial treatment of hospitalized VAMC patients with CDIs.
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http://dx.doi.org/10.1002/phar.2503DOI Listing
February 2021

Outpatient Subcutaneous Antimicrobial Therapy (OSCAT) as a Measure to Improve the Quality and Efficiency of Healthcare Delivery for Patients With Serious Bacterial Infections.

Front Med (Lausanne) 2020 23;7:585658. Epub 2020 Dec 23.

CHU de Bordeaux, Pôle de Gérontologie Clinique, Bordeaux, France.

Since the 1970s, outpatient parenteral antimicrobial therapy (OPAT) has been a viable option for patients who require intravenous antibiotics when hospitalization is not warranted. While the benefits of OPAT as a measure to improve the efficiency of healthcare delivery (i.e., reduced hospital days) and patient satisfaction are well-documented, OPAT is associated with a number of challenges, including line complications and reliance on daily healthcare interactions in some cases at home or in a clinic. To minimize the continued need for intensive healthcare services in the outpatient setting, there is trend toward patients self-administering antibiotics at home without the presence of healthcare workers, after adequate training. In most cases, patients administer the antibiotics through an established intravenous catheter. While this OPAT practice is becoming more accepted as a standard of care, the potential for line complications still exists. Outpatient subcutaneous antimicrobial therapy (OSCAT) has become an increasingly accepted alternative route of administration of antibiotics to IV by French infectious diseases physicians and geriatricians; however, currently, no antibiotics are approved to be administered subcutaneously. Antibiotics with longer half-lives that are completely absorbed and have a favorable local tolerability profile are ideal candidates for OSCAT and have the potential to maximize the quality and efficiency of parenteral antibiotic delivery in the outpatient setting. The increasing development of wearable, on-body subcutaneous delivery systems make OSCAT even more viable as they increase patient independence while avoiding line complications and potentially removing the need for direct healthcare professional observation.
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http://dx.doi.org/10.3389/fmed.2020.585658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785854PMC
December 2020

Vancomycin Area Under the Curve-guided Dosing and Monitoring: "Is the Juice Worth the Squeeze"?

Pharmacotherapy 2020 12;40(12):1176-1179

Pharmacometrics Center of Excellence, Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.

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http://dx.doi.org/10.1002/phar.2482DOI Listing
December 2020

Use of Oral Tetracyclines in the Treatment of Adult Patients with Community-Acquired Bacterial Pneumonia: A Literature Review on the Often-Overlooked Antibiotic Class.

Antibiotics (Basel) 2020 Dec 14;9(12). Epub 2020 Dec 14.

Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.

Oral tetracyclines have been used in clinical practice for over 60 years. Overall, one of the most common indications for use of oral tetracyclines is for treatment of adult outpatients with lower respiratory tract infections, including community-acquired pneumonia (CAP). Despite the longstanding use of oral tetracyclines, practice patterns indicate that they are often considered after other guideline-concordant oral CAP treatment options (namely macrolides, fluoroquinolones, and β-lactams). However, there are growing resistance or safety concerns with the available oral agents listed for outpatients with CAP in the updated American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) CAP guidelines, especially among patients with comorbidities or notable risk factors for resistant pathogens. Given the need for alternative oral agents to macrolides, fluoroquinolones, and beta-lactams for adult outpatients with CAP, this review summarizes the literature on the use of oral tetracyclines (i.e., doxycycline, minocycline, and omadacycline) for this indication. As part of this review, we described their mechanism of action, common mechanisms of resistance, susceptibility profiles against common CAP pathogens, pharmacokinetics, pharmacodynamics, clinical data, and safety. The intent of the review is to highlight the important considerations when deciding between doxycycline, minocycline, and omadacycline for an adult outpatient with CAP in situations in which use of an oral tetracycline is warranted.
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http://dx.doi.org/10.3390/antibiotics9120905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764829PMC
December 2020

The Pharmacodynamic-Toxicodynamic Relationship of AUC and in Vancomycin-Induced Kidney Injury in an Animal Model.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC] and maximum concentration from 0 to 24 h [ ]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; = 0.96). KIM-1 values were greater in QD and BID groups ( for QD versus TID, <0.002; for QD versus QID, <0.004; for BID versus TID, <0.002; and for BID versus QID, <0.004). Exposure-response relationships were observed between KIM-1 versus and AUC ( = 0.7 and 0.68). Corrected Akaike's information criterion showed as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95). While PK-TD indices are often intercorrelated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.
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http://dx.doi.org/10.1128/AAC.01945-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092494PMC
February 2021

Questions on Vancomycin Dosing.

Clin Infect Dis 2021 10;73(7):e1777-e1778

University of Arkansas for Medical Sciences College of Pharmacy and Arkansas Children's Hospital, Little Rock, Arkansas, USA.

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http://dx.doi.org/10.1093/cid/ciaa1775DOI Listing
October 2021

Intraclass Difference in Pneumonia Risk with Fluticasone and Budesonide in COPD: A Systematic Review of Evidence from Direct-Comparison Studies.

Int J Chron Obstruct Pulmon Dis 2020 11;15:2889-2900. Epub 2020 Nov 11.

Department of Medicine, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA.

Background: Inhaled corticosteroids (ICS) are widely used and recommended to treat chronic obstructive pulmonary disease (COPD). While generally considered safe, several studies demonstrated an increased risk of pneumonia with the use of ICS in COPD patients. Although all ICS indicated for COPD carry the class labeling warning of increased pneumonia risk, evidence suggests an intraclass difference in the risk of pneumonia between inhaled budesonide and fluticasone. To date, systematic reviews of direct-comparison studies have not been performed to assess if an intraclass difference exists.

Research Question: This review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most commonly used ICS in COPD.

Study Design And Methods: A search of the medical literature was conducted in PubMed and Embase for the time period of 01/01/69-05/31/19. The search strategy combined terms that defined the patient/disease type, exposures, outcome, and the study/publication type. Descriptive and comparative statistics reported for fluticasone- and budesonide-containing products in each study, including data for pneumonia event subgroups, were extracted and reported by dose, seriousness, or practice setting. Controlled clinical trials and observational studies meeting the inclusion criteria were assessed for methodologic quality by using the appropriate tool from the list of study quality assessment tools developed by the National Institutes of Health.

Results: The summary relative risk (RR) ratio across 5 included studies (57,199 patients) was 1.13 (95% CI: 1.09-1.19), representing a 13.5% increased risk of pneumonia among fluticasone users compared to budesonide users. Similarly, summary RR ratio for serious pneumonia implied a 14.4% increased risk of serious pneumonia among fluticasone users compared to budesonide users (pooled RR: 1.14; 95% CI: 1.09-1.20).

Interpretation: There is likely a clinically important intraclass difference in the risk of pneumonia between fluticasone- and budesonide-containing inhaled medications in COPD.
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http://dx.doi.org/10.2147/COPD.S269637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667513PMC
June 2021

Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Northwestern University, Chicago, Illinois, USA.

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [AUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (f) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with f). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.
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http://dx.doi.org/10.1128/AAC.01809-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092545PMC
February 2021

Impact of Incremental Delays in Appropriate Therapy on the Outcomes of Hospitalized Adult Patients with Gram-negative Bloodstream Infections: "Every day matters".

Pharmacotherapy 2020 09 18;40(9):889-901. Epub 2020 Aug 18.

Shionogi Inc, Florham Park, New Jersey, USA.

Background: Serious bloodstream infections (BSIs) are often caused by Gram-negative (GN) bacteria in hospitalized patients. Treatment of these infections has been further complicated by the continued rise and spread of drug-resistant pathogens, including carbapenem resistant (CR) strains of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.

Methods: This retrospective cohort analysis used real-world data from a large United States hospital-based database to examine the association between key clinical outcomes and different lengths of time to appropriate treatment between October 2010 and September 2015.

Results: Of 40,549 patients with GN-BSIs who were identified, 1117 (2.8%) had a CR GN-BSI. Overall, outcomes of hospitalized adult patients with GN-BSIs incrementally worsened the longer appropriate therapy was delayed. Patients with CR GN-BSIs had a median infection-associated length of stay (LOS) of 8, 9, 10, and 13 days, whereas patients with CS GN-BSIs had a median infection-associated LOS of 6, 7, 8, and 11 days for patients with days to appropriate therapy of 0, 1-2, 3-4, and ≥ 5 days, respectively. Among patients with CR GN-BSIs, the percentage of patients discharged home was 38%, 33%, 35%, and 31%, whereas in patients with CS GN-BSIs, the percentage of patients discharged home was 58%, 53%, 48%, and 43% for patients with days to appropriate therapy of 0, 1-2, 3-4, and ≥ 5 days, respectively.

Conclusion: The findings from this study highlight the clear need to deliver appropriate therapy more expeditiously in patients with CS and CR GN-BSIs.
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http://dx.doi.org/10.1002/phar.2446DOI Listing
September 2020

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

Lancet Infect Dis 2021 02 12;21(2):226-240. Epub 2020 Oct 12.

Shionogi, Osaka, Japan. Electronic address:

Background: New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.

Methods: We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).

Findings: Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.

Interpretation: Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.

Funding: Shionogi.
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http://dx.doi.org/10.1016/S1473-3099(20)30796-9DOI Listing
February 2021

Using Therapeutic Drug Monitoring to Treat KPC-Producing Central Nervous System Infection With Ceftazidime/Avibactam.

Open Forum Infect Dis 2020 Sep 18;7(9):ofaa349. Epub 2020 Aug 18.

Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.

This report describes the treatment of carbapenemase (KPC)-3-producing multidrug-resistant with ceftazidime/avibactam (CAZ-AVI) in a patient who developed postneurosurgical meningitis and bacteremia. Therapeutic drug monitoring of cerebrospinal fluid and blood samples demonstrated CAZ-AVI concentration levels 20-fold greater than the minimum inhibitory concentration in the first 60 minutes postinfusion, providing evidence for the utility of CAZ-AVI in treating KPC- central nervous system infections.
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http://dx.doi.org/10.1093/ofid/ofaa349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491706PMC
September 2020

Hospital Admission Patterns in Adult Patients with Community-Acquired Pneumonia Who Received Ceftriaxone and a Macrolide by Disease Severity across United States Hospitals.

Antibiotics (Basel) 2020 Sep 4;9(9). Epub 2020 Sep 4.

Paratek Pharmaceuticals, Inc. 1000 1st Avenue, King of Prussia, PA 19406, USA.

(1) Objective: There are limited data regarding community-acquired pneumonia (CAP) admissions patterns in US hospitals. Current expert CAP guidelines advocate for outpatient treatment or an abbreviated hospital stay for CAP patients in pneumonia severity index (PSI) risk classes I-III (low risk); however, the extent of compliance with this recommendation is unclear. This study sought to estimate the proportion of admissions among CAP patients who received ceftriaxone and macrolide therapy, one of the most commonly prescribed guideline-concordant CAP regimens, by PSI risk class and Charlson comorbidity index (CCI) score. (2) Methods: A retrospective cross-sectional study of patients in the Vizient (MedAssets, Irving, Texas) database between 2012 and 2015 was performed. Patients were included if they were aged ≥ 18 years, had a primary diagnosis for CAP, and received ceftriaxone and a macrolide on hospital day 1 or 2. Baseline demographics and admitting diagnoses were used to calculate the PSI score. Patients in the final study population were grouped into categories by their PSI risk class and CCI score. Hospital length of stay, 30-day mortality rates, and 30-day CAP-related readmissions were calculated across resulting PSI-CCI strata. (3) Results: Overall, 32,917 patients met the study criteria. Approximately 70% patients were in PSI risk classes I-III and length of stay ranged between 4.9 and 6.2 days, based on CCI score. The 30-day mortality rate was <0.5% and <1.4% in patients with PSI risk classes I and II, respectively. (4) Conclusions: Over two-thirds of hospitalized patients with CAP who received ceftriaxone and a macrolide were in PSI risk classes I-III. Although the findings should be interpreted with caution, they suggest that there is a potential opportunity to improve the efficiency of healthcare delivery for CAP patients by shifting inpatient care to the outpatient setting in appropriate patients.
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http://dx.doi.org/10.3390/antibiotics9090577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557926PMC
September 2020

The Pharmacokinetic and Pharmacodynamic Properties of Hydroxychloroquine and Dose Selection for COVID-19: Putting the Cart Before the Horse.

Infect Dis Ther 2020 Sep 1;9(3):561-572. Epub 2020 Aug 1.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.

Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.
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http://dx.doi.org/10.1007/s40121-020-00325-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395206PMC
September 2020

Effect of Vancomycin-Associated Acute Kidney Injury on Incidence of 30-Day Readmissions among Hospitalized Veterans Affairs Patients with Skin and Skin Structure Infections.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

Department of Pharmacy, Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York, USA

Among hospitalized adults who received vancomycin for their skin and skin structure infection (SSSI), patients who experienced acute kidney injury (AKI) had considerably higher 30-day readmission rates. Nearly half of the observed 30-day readmissions were due to non-SSSI-related reasons, which is consistent with the persistent organ dysfunction observed among patients with AKI.
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http://dx.doi.org/10.1128/AAC.01268-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508587PMC
September 2020

Vancomycin Area Under the Curve to Predict Timely Clinical Response in the Treatment of Methicillin-resistant Staphylococcus aureus Complicated Skin and Soft Tissue Infections.

Clin Infect Dis 2020 Jul 27. Epub 2020 Jul 27.

Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.

Introduction: Although recent guidelines have recommended monitoring vancomycin (VAN) area under the curve (AUC)/minimum inhibitory concentration (MIC) to ensure clinical efficacy and minimize toxicity in methicillin-resistant Staphylococcus aureus (MRSA) for various infections, there are no recommendations regarding complicated skin and soft tissue infections (cSSTIs). We aimed to evaluate the association between VAN AUC and clinical outcomes in MRSA cSSTIs.

Methods: This was a retrospective cohort study of adult patients treated with ≥ 72 hours of VAN for MRSA cSSTI from 2008-2013 at Detroit Medical Center. The primary outcome was timely clinical success (TCS) defined as 1) resolution of signs and symptoms of infection within 72 hours, 2) stabilization and/or reduction in lesion size, 3) alternative agents not required due to VAN failure or toxicity as elected by the prescribing clinician. Classification and regression tree (CART) analysis was performed to determine the AUC associated with TCS in the cohort. Multivariable logistic regression was used to evaluate the association between VAN-AUC and the primary outcome.

Results: A total of 154 patients were included in this analysis. CART identifed an AUC ≥435 mg*hr/L for TCS. Overall, 60.9% of patients experienced TCS; 69.7% in the target-AUC group vs. 52.5% in the below-target AUC group, (P=0.013). Target-AUC attainment was independently associated with increased odds of TCS ([aOR], 2.208; 95% [CI], 1.047 -4.659).

Discussion: In adults treated with VAN for MRSA cSSTI, target-AUC attainment was independently associated with improved clinical outcomes and maybe most warrated for patients at high risk of VAN-failure or VAN-associated toxicity.
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http://dx.doi.org/10.1093/cid/ciaa1039DOI Listing
July 2020

Approach to the Treatment of Patients with Serious Multidrug-Resistant Pseudomonas aeruginosa Infections.

Pharmacotherapy 2020 09 17;40(9):952-969. Epub 2020 Aug 17.

Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.

Multidrug resistance(MDR) among Pseudomonas aeruginosa (PSA) isolates presents a significant clinical challenge and can substantially complicate the approach to selection of optimal antibiotic therapy. This review addresses major considerations in antibiotic selection for patients with suspected or documented serious MDR-PSA infections. Common mechanisms contributing to MDR among clinical PSA isolates are summarized. Empiric and definitive therapy considerations are addressed including the potential role of combination therapy. Newer agents with in vitro activity against MDR-PSA (e.g., ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and cefiderocol) and their potential roles in clinical settings are discussed. Although these newer agents are promising options for the treatment of MDR-PSA, clinical data remain generally limited. Future studies are needed to determine optimal agents for the empiric and definitive treatment of MDR-PSA.
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http://dx.doi.org/10.1002/phar.2449DOI Listing
September 2020

Intravenous Compatibility of Ceftazidime-Avibactam and Aztreonam Using Simulated and Actual Y-site Administration.

Clin Ther 2020 08 16;42(8):1580-1586.e2. Epub 2020 Jul 16.

Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.

Purpose: The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration.

Methods: Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate.

Findings: Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments.

Implications: Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.
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http://dx.doi.org/10.1016/j.clinthera.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428177PMC
August 2020
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