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1.
Am J Clin Dermatol ; 25(4): 655-668, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38743155

ABSTRACT

BACKGROUND: Pediatric patients with moderate-to-severe atopic dermatitis (AD) often experience a high disease burden and have a high risk of persistent disease. Standard-of-care immunosuppressive systemic treatments have been used off-label for AD in pediatric patients despite concerns for suboptimal safety with continuous use and risk of relapse upon discontinuation. The biologic agent dupilumab is the first systemic treatment approved for moderate-to-severe AD in children as young as 6 months. Long-term safety and efficacy data in this patient population are needed to inform continuous AD management. OBJECTIVES: The purpose of this work was to determine the long-term safety and efficacy of dupilumab treatment up to 1 year in an open-label extension (OLE) study [LIBERTY AD PED-OLE (NCT02612454)] in children aged 6 months to 5 years with moderate-to-severe AD who previously participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434 part B; parent study) and were subsequently enrolled in PED-OLE. METHODS: In PED-OLE, patients received dupilumab every 4 weeks according to a weight-tiered regimen (body weight ≥ 5 kg to < 15 kg: 200 mg; ≥ 15 kg to < 30 kg: 300 mg). RESULTS: Data for 142 patients were analyzed, 60 of whom had completed the 52-week visit at time of database lock. Mean age at baseline was 4.1 y [SD, 1.13; range, 1.0-5.9 years]. A majority (78.2%) of patients reported ≥ 1 treatment-emergent adverse event (TEAE), most of which were mild or moderate and transient. The most frequently reported TEAEs were nasopharyngitis (19.7%), cough (15.5%), and pyrexia (14.1%). One TEAE led to treatment discontinuation (severe urticaria, which resolved in 1 day). By week 52, 36.2% of patients had achieved an Investigator's Global Assessment score of 0/1 (clear/almost clear skin), and 96.6%, 79.3%, and 58.6% had at least 50%, 75%, or 90% improvement, respectively, in Eczema Area and Severity Index scores. CONCLUSIONS: Consistent with results seen in adults, adolescents, and older children (aged 6-11 years), treatment with dupilumab for up to 1 year in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD demonstrated an acceptable long-term safety profile and sustained efficacy. These results support the long-term continuous use of dupilumab in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02612454 and NCT03346434 (part B).


Atopic dermatitis (AD) is a chronic inflammatory skin disease that often results in a high disease burden in young children and their families. Patients often need long-term treatment to control their disease symptoms, including itch and rash. Dupilumab treatment for 16 weeks has shown benefits in children aged 6 months to 5 years with moderate-to-severe AD, with an acceptable safety profile. As AD is likely to continue from childhood into adolescence and adulthood, there is a need for data supporting long-term use of dupilumab in young children. In this study, children who completed the 16-week study continued dupilumab treatment for up to 1 year, receiving 200 mg or 300 mg of dupilumab (depending on the child's bodyweight) every 4 weeks. Through the year of treatment, 78.2% of patients reported at least one side effect, most of which were mild or moderate. Only one patient interrupted treatment because of severe skin rash (hives), which was resolved in 1 day. At the end of the year, 36.2% of patients had clear or almost clear skin, and almost all (96.6%) achieved at least 50% improvement in their extent and severity of disease. Additionally, 79.3%, and 58.6% had at least 75% or 90% improvement in their extent and severity of disease. In summary, consistent with results seen in adults, adolescents, and older children, this study showed that 1-year dupilumab treatment provides continued benefits with an acceptable safety profile. These results support long-term continuous use of dupilumab in children aged 6 months to 5 years with moderate-to-severe AD. What is the long-term safety and efficacy profile in young children with moderate-to-severeatopic dermatitis treated with dupilumab?


Subject(s)
Antibodies, Monoclonal, Humanized , Dermatitis, Atopic , Severity of Illness Index , Humans , Dermatitis, Atopic/drug therapy , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Female , Male , Child, Preschool , Infant , Treatment Outcome , Injections, Subcutaneous , Nasopharyngitis/chemically induced , Drug Administration Schedule , Time Factors , Double-Blind Method , Interleukin-4 Receptor alpha Subunit/antagonists & inhibitors
2.
Surg Infect (Larchmt) ; 22(4): 447-449, 2021 May.
Article in English | MEDLINE | ID: mdl-32931362

ABSTRACT

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections and their recurrences. Although traditionally not considered for use against MRSA, cefazolin presents a possible option when administered using ultrasonic drug dispersion (UD2). This novel technique localizes delivery of drug into the subcutaneous tissue and achieves concentrations that exceed the minimum inhibitory concentrations (MICs) of most clinical MRSA isolates. The purpose of this study was to evaluate the impact of achievable cefazolin concentrations on the rate and extent of bactericidal activity using time-kill methodologies Materials and Methods: The cefazolin MICs of the four MRSA isolates selected for this in vitro time-kill study were 64, 128, 256, and 512 mg/L. Duplicates of drug-free control and cefazolin experiments were carried out using the average UD2-achievable cefazolin concentration (1,300 mg/L). Experiments were incubated at 37°C throughout each run. Samples were plated and incubated for 18 to 24 hours. The lower limit of detection of colony forming units per milliliter (CFU/mL) was 1.7 log10 CFU/mL. Cefazolin was considered bactericidal when it decreased bacterial density by ≥3 log10 CFU/mL from the initial inoculum after 24 hours of incubation. Results: Cefazolin produced mean 24-hour CFU changes of -4.39 to -4.89 log10 CFU/mL against MRSA isolates with MICs from 64 to 512 mg/L. Cefazolin demonstrated bactericidal activity against all studied MRSA isolates and no regrowth was observed at 24 hours. Conclusions: The mean cefazolin tissue concentration achieved by UD2 was bactericidal against four MRSA isolates. Further investigation is warranted to assess the utility of UD2-administered cefazolin against MRSA skin and soft tissue infections.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Soft Tissue Infections , Anti-Bacterial Agents/pharmacology , Cefazolin/pharmacology , Humans , Microbial Sensitivity Tests
3.
Antimicrob Agents Chemother ; 64(12)2020 11 17.
Article in English | MEDLINE | ID: mdl-33139283

ABSTRACT

Combination therapy may enhance imipenem/cilastatin/relebactam's (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were -2.52 ± 0.49, -1.49 ± 0.49, -1.15 ± 0.67, and -0.61 ± 0.10 log10 CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 µg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic (n = 1) or additive (n = 2) interactions against three isolates with 24-h CFU reductions ranging from -2.62 to -4.67 log10 CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving -0.51- to -3.33-log10 CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant P. aeruginosa, I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some P. aeruginosa, whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.


Subject(s)
Imipenem , Pseudomonas aeruginosa , Amikacin/pharmacology , Anti-Bacterial Agents/pharmacology , Azabicyclo Compounds , Cilastatin/pharmacology , Colistin/pharmacology , Drug Resistance, Multiple, Bacterial , Drug Synergism , Humans , Imipenem/pharmacology , Microbial Sensitivity Tests
4.
Antibiotics (Basel) ; 9(7)2020 Jul 09.
Article in English | MEDLINE | ID: mdl-32659898

ABSTRACT

Augmented renal clearance (ARC) refers to the state of heightened renal filtration commonly observed in the critically ill. Its prevalence in this patient population is a consequence of the body's natural response to serious disease, as well as the administration of fluids and pharmacologic therapies necessary to maintain sufficient blood pressure. ARC is objectively defined as a creatinine clearance of more than 130 mL/min/1.73 m2 and is thus a crucial condition to consider when administering antibiotics, many of which are cleared renally. Using conventional dosing regimens risks the possibility of subtherapeutic concentrations or clinical failure. Over the past decade, research has been conducted in patients with ARC who received a number of antibacterials frequently used in the critically ill, such as piperacillin-tazobactam or vancomycin. Strategies to contend with this condition have also been explored, though further investigations remain necessary.

5.
Clin Ther ; 42(4): 606-613, 2020 04.
Article in English | MEDLINE | ID: mdl-32139176

ABSTRACT

PURPOSE: Meropenem and vaborbactam is an intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic active against multidrug resistant gram-negative bacteria. It may be a suitable treatment for inpatient and outpatient management of infections, and the intravenous admixture stability is therefore important for optimal utilization. The purpose of this study was to determine the stability of meropenem and vaborbactam in polyvinyl chloride (PVC) infusion bags and elastomeric pumps at room and refrigerated temperatures. METHODS: Meropenem and vaborbactam vials were reconstituted according to manufacturer instructions and diluted in PVC infusion bags to final concentrations of 4, 8, and 16 mg/mL and in elastomeric pumps to 11.4 mg/mL (n = 5 replicates per concentration and per temperature). PVC bags and elastomeric pumps were stored at room temperature (~24 °C) or in the refrigerator (~4 °C) and sampled over 12 and 144 h, respectively. Stability was defined as the duration that meropenem and vaborbactam concentrations remained ≥90% of the original concentrations. FINDINGS: All room temperature replicates across the tested concentrations retained meropenem and vaborbactam stability over 12 h and displayed concentration-dependent degradation. Refrigerated studies resulted in meropenem and vaborbactam stability at all tested concentrations up to 120 h. IMPLICATIONS: Meropenem and vaborbactam in PVC bags (4, 8, and 16 mg/mL) and elastomeric pumps (11.4 mg/mL) were stable for 12 h at room temperature and 120 h when refrigerated. These stability data allow for enhanced flexibility in the preparation, storage, wastage, and administration of meropenem and vaborbactam in the hospital and outpatient setting.


Subject(s)
Anti-Bacterial Agents/chemistry , Boronic Acids/chemistry , Heterocyclic Compounds, 1-Ring/chemistry , Meropenem/chemistry , Drug Combinations , Drug Stability , Elastomers , Infusion Pumps , Infusions, Intravenous/instrumentation , Polyvinyl Chloride , Refrigeration , Temperature
6.
Antimicrob Agents Chemother ; 63(12)2019 09 09.
Article in English | MEDLINE | ID: mdl-31591126

ABSTRACT

Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of ß-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.

7.
J Clin Microbiol ; 57(12)2019 12.
Article in English | MEDLINE | ID: mdl-31533981

ABSTRACT

Blood cultures are routinely collected in pairs of aerobic and anaerobic bottles. Artificial sterilization of Gram-negative bacteria in aerobic bottles containing clinically meaningful antibiotic concentrations has previously been observed. This study assessed recovery from anaerobic bottles with and without antibiotic binding resins. We studied the recovery of Escherichia coli and Klebsiella pneumoniae when exposed to meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam in resin-containing BacT/Alert FN Plus and BD Bactec Plus anaerobic/F bottles as well as resin-free BacT/Alert SN and BD Bactec standard anaerobic bottles. Bottles were inoculated with bacteria and whole blood containing peak, midpoint, or trough concentrations and incubated for up to 120 hours in their respective detection systems. In E. coli resin-containing bottles, recovery was observed in 10/24 (42%), 17/24 (71%), and 18/24 (75%) (P = 0.034) of those exposed to peak, midpoint, and trough concentrations, respectively. In K. pneumoniae resin-containing bottles, recovery was observed in 8/16 (50%), 10/16 (63%), and 10/16 (63%) (P = 0.710), respectively. No growth was detected in bottles containing cefepime regardless of concentration, while recovery was observed in the presence of all concentrations of cefazolin and piperacillin-tazobactam. Recovery in bottles with meropenem and imipenem was more frequently observed in BacT/Alert FN Plus bottles compared with Bactec Plus bottles. Resin-free bottles demonstrated significantly lower recovery than bottles containing binding resin. Clinical concentrations of certain antibiotics can adversely affect detection of E. coli and K. pneumoniae in anaerobic blood culture bottles. Obtaining blood cultures immediately before a dose and utilizing resin-containing anaerobic bottles will maximize the likelihood of recovery.


Subject(s)
Anti-Bacterial Agents/isolation & purification , Bacteremia/diagnosis , Blood Culture/methods , Escherichia coli/isolation & purification , Klebsiella pneumoniae/isolation & purification , Plasma/chemistry , Anaerobiosis , Escherichia coli Infections/diagnosis , Humans , Klebsiella Infections/diagnosis , Sensitivity and Specificity
8.
Clin Ther ; 41(10): 2162-2170, 2019 10.
Article in English | MEDLINE | ID: mdl-31506218

ABSTRACT

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.


Subject(s)
Anti-Bacterial Agents/chemistry , Chemistry, Pharmaceutical , Tetracyclines/chemistry , Anti-Bacterial Agents/administration & dosage , Drug Incompatibility , Humans , Infusions, Intravenous , Sodium Chloride/chemistry , Tetracyclines/administration & dosage
9.
J Clin Microbiol ; 57(10)2019 10.
Article in English | MEDLINE | ID: mdl-31340990

ABSTRACT

Blood culture bottles containing antibiotic binding resins are routinely used to minimize artificial sterilization in the presence of antibiotics. However, the resin binding kinetics can differ between antibiotics and concentrations. This study assessed the impact of clinically meaningful peak, midpoint, and trough concentrations of meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam on the recovery of Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae from resin-containing BacT/Alert FA Plus and Bactec Aerobic/F blood culture bottles. P. aeruginosa-inoculated bottles alarmed positive in 4/20 (20%), 16/20 (80%), and 20/20 (100%) of those with peak, midpoint, and trough concentrations of antipseudomonal agents, respectively (P ≤ 0.001). E. coli was recovered from 8/24 (33%), 11/24 (46%), and 14/24 (58%) of bottles with peak, midpoint, and trough concentrations, respectively (P = 0.221). K. pneumoniae was recovered from 8/16 (50%) at all concentrations of the studied antibiotics (P = 1.0). BacT/Alert and Bactec bottles inoculated with antibiotics and P. aeruginosa had similar times to detection (TTD) (P = 0.352); however, antibiotic-containing BacT/Alert bottles had a shorter TTD compared with antibiotic-containing Bactec bottles for E. coli (P = 0.026) and K. pneumoniae (P ≤ 0.001). Pathogen recovery in BacT/Alert FA Plus and Bactec Aerobic/F blood culture bottles containing antibiotic binding resins was greatly reduced in the presence of antibiotics, especially at higher concentrations. These data support the practice of drawing blood cultures immediately before an antibiotic dose to maximize the chances of pathogen recovery.


Subject(s)
Anti-Bacterial Agents/pharmacology , Fluoroquinolones/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/isolation & purification , beta-Lactams/pharmacology , Bacteriological Techniques , Blood Culture , Critical Illness , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Humans , Microbial Sensitivity Tests
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