Review of fluconazole treatment and prophylaxis for invasive candidiasis in neonates.
Invasive candidiasis accounts for approximately 10% of nosocomial infections in preterm infants, with an incidence of 1% to 4% among neonatal intensive care unit (NICU) admissions and a mortality as high as 20% to 30%. These outcomes warrant improved treatment and prevention strategies for infants at highest risk. The Infectious Diseases Society of America provides guidelines on antifungal medications for the prophylaxis and treatment of candidiasis in NICUs; however, there are still variations in practice on the use of fluconazole for prophylaxis and treatment of invasive candidiasis. This review provides specific information regarding fluconazole activity, pharmacokinetics, and a literature evaluation of dosing strategies and comparisons to other treatments in the neonatal population.
Hornik CD; Bondi DS; Greene NM; Cober MP; John B
Journal Of Pediatric Pharmacology & Therapeutics
2021
2021-02-15
Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2021.
review
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.5863/1551-6776-26.2.115">http://doi.org/10.5863/1551-6776-26.2.115</a></td>
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Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.
Study participants were stratified to G143E non-carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography–tandem mass spectrometry (LC–MS/MS) method.
Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers.
Her LH; Wang X; Shi J; Choi HJ; Jung SM; Smith LS; Wu AH; Bleske Barry E; Zhu H-J
British Journal Of Clinical Pharmacology
2021
2021-05-07
Journal Article
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1111/bcp.14888">http://doi.org/10.1111/bcp.14888</a></td>
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Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.
pharmacokinetics; angiotensin-converting enzyme (ACE) inhibitors; Carboxylesterase1 (CES1); enalapril; pharmacogenetics
Background and Objective: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics, and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers.; Methods: Study participants were stratified to G143E non-carriers (n=15) and G143E carriers (n=6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72h PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established LC-MS/MS method.; Results: The CES1 G143E carriers had 30.9% lower enalaprilat C max (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC 0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*hr/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC 0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers.; Conclusions: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers. (This article is protected by copyright. All rights reserved.)
Her LH; Wang X; Shi J; Choi HJ; Jung SM; Smith LS; Wu AH; Bleske Barry E; Zhu H-J
British Journal Of Clinical Pharmacology
2021
2021-05-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1111/bcp.14888" target="_blank" rel="noreferrer noopener">10.1111/bcp.14888</a>
Review of fluconazole treatment and prophylaxis for invasive candidiasis in neonates.
amphotericin B; antifungal agents; Candida; candidiasis; DENTAL prophylaxis; fluconazole; FLUCONAZOLE; INVASIVE candidiasis; NEONATAL intensive care units; newborn; pharmacokinetics; PHARMACOKINETICS; PREMATURE infants
Invasive candidiasis accounts for approximately 10% of nosocomial infections in preterm infants, with an incidence of 1% to 4% among neonatal intensive care unit (NICU) admissions and a mortality as high as 20% to 30%. These outcomes warrant improved treatment and prevention strategies for infants at highest risk. The Infectious Diseases Society of America provides guidelines on antifungal medications for the prophylaxis and treatment of candidiasis in NICUs; however, there are still variations in practice on the use of fluconazole for prophylaxis and treatment of invasive candidiasis. This review provides specific information regarding fluconazole activity, pharmacokinetics, and a literature evaluation of dosing strategies and comparisons to other treatments in the neonatal population. [ABSTRACT FROM AUTHOR]
Hornik CD; Bondi DS; Greene NM; Cober MP; John B
Journal Of Pediatric Pharmacology & Therapeutics
2021
2021-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.5863/1551-6776-26.2.115" target="_blank" rel="noreferrer noopener">10.5863/1551-6776-26.2.115</a>
In Vivo Pharmacokinetics And Biodistribution Of Novel All-trans Retinoic Acid Derivative-loaded, Folate-modified Poly (l-amino Acid) Micelles
cancer; cellular uptake; copolymer micelles; Drug; drug-delivery; Folate; nanoparticles; nanoparticles; Pharmacokinetics; Pharmacology & Pharmacy; polymeric micelles; targeted delivery; targeting; Tissue distribution
Folate is widely used as a target ligand for tumor cells, and poly (L-aspartic acid)-b-poly-(L-phenylalanine) (PAA-PPA) is a biodegradable material with low immunogenicity and toxicity. In this study, to enhance the targeting effect, folate-conjugated PAA-PPA micelles were synthesized. To evaluate the hypothesis, we assessed the pharmacokinetics and biodistribution of.a new antitumor drug 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) loaded into the micelles. We also observed in vivo imaging of 1,1'-dioctadecy1-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) loaded micelles to confirm distribution. The results showed that ATPR-loaded, folate-modified PAA-PPA displayed a prolonged circulation half-life and iinproved the targeting effect. (C) 2017 Elsevier B.V. All tights reserved.
Hong W X; Hu R F; Huang X C; Lu X Q; Czech T; Tang J H
Journal of Drug Delivery Science and Technology
2017
2017-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jddst.2017.09.007" target="_blank" rel="noreferrer noopener">10.1016/j.jddst.2017.09.007</a>
Treatment Of Bacterial Skin And Soft-tissue Infections
bypass-surgery; diabetic foot infections; disease; moxalactam; Obstetrics & Gynecology; pharmacokinetics; plus clavulanic acid; recurrent cellulitis; resistance; staphylococci; Surgery; timentin
File T M; Tan J S
Surgery Gynecology & Obstetrics
1991
1991
Journal Article or Conference Abstract Publication
n/a
Ticarcillin-clavulanate Therapy For Bacterial Skin And Soft-tissue Infections
acid; Immunology; Microbiology; moxalactam; penetration; pharmacokinetics; potassium; safety; timentin
File T M; Tan J S
Reviews of Infectious Diseases
1991
1991-07
Journal Article or Conference Abstract Publication
n/a
A PRACTICAL APPROACH TO ANTIBIOTIC-TREATMENT IN WOMEN TAKING ORAL-CONTRACEPTIVES
pharmacokinetics; pregnancy; tetracycline; Dermatology; estradiol; rifampicin; ampicillin; drug-interactions; enterohepatic circulation; norethisterone; norgestimate
Clinical situations that require the use of systemic antibiotic therapy are common. Because millions of women choose oral contraceptives for birth control, the potential for interaction between these drugs frequently has to be considered. We review the available information and present a practical approach for dealing with this situation based on sharing responsibility with an educated patient.
Miller D M; Helms S E; Brodell R T
Journal of the American Academy of Dermatology
1994
1994-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/s0190-9622(94)70127-x" target="_blank" rel="noreferrer noopener">10.1016/s0190-9622(94)70127-x</a>
CDNA-DIRECTED EXPRESSION OF HUMAN CYTOCHROME-P450 CYP3A4 USING BACULOVIRUS
pharmacokinetics; Pharmacology & Pharmacy; metabolism; polymorphism; identification; reductase; oxidation; vaccinia virus; human-liver; catalytic activities; hydroxylation
A recombinant baculovirus containing the human CYP3A4 cDNA was constructed and used to express CYP3A4 in SF9 insect cells (0.46 +/- 0.13 nmol/mg protein, 103 +/- 29 nmol/liter, N = 15). The enzyme represented similar to 2-3% of total cellular protein and could be purified by a two column procedure to a specific content of 12.7 nmol/mg protein. Catalytic activity of the purified enzyme after reconstitution was optimum using molar ratios of CYP3A4 to cytochrome b(5) to NADPH-P450 oxidoreductase of 1:3:20, respectively. The enzyme metabolized cortisol, erythromycin, testosterone, and (R)-warfarin. Recombinant baculovirus expresses the highest amounts of all expression systems published to date of catalytically intact CYP3A4. This system is an excellent alternative for the isolation and characterization of P450 forms from human liver.
Buters J T M; Korzekwa K R; Kunze K L; Omata Y; Hardwick J P; Gonzalez F J
Drug Metabolism and Disposition
1994
1994-09
Journal Article or Conference Abstract Publication
n/a
CEFADROXIL, CEFACLOR, CEFUROXIME - INTERSTITIAL FLUID CONCENTRATIONS DETERMINED THROUGH A SKIN WINDOW
cefaclor; cefadroxil; cefuroxime; interstitial fluid; pharmacokinetics; Pharmacology & Pharmacy; Research & Experimental Medicine; skin window
The complex interaction between plasma and tissue concentrations of drug has significant implications for therapies that use beta-lactam antibiotics. This comparative, triple-crossover, open-label study enrolled 12 healthy adult male volunteers to determine interstitial fluid concentrations of cefadroxil, cefaclor, and cefuroxime. Each participant, by random assignment, received therapeutically equivalent (in skin and skin-structure infections) single oral doses of cefadroxil 500 mg, cefaclor 250 mg, and cefuroxime axetil 250 mg on separate occasions 1 week apart. Serum and interstitial fluid (by skin-window technique) concentrations were assayed sequentially to determine persistence and magnitude of antibiotic penetration into interstitial fluid. Statistically higher concentrations of cefadroxil (5.5 mug/mL) than of cefaclor (1.2 mug/mL) and cefuroxime (1.1 mug/mL) were documented in interstitial fluid. Cefadroxil (0.63) also demonstrated a tissue fluid:blood area under the curve ratio significantly greater than that achieved by cefaclor (0.48) and comparable to that of cefuroxime axetil (0.60). No significant adverse events occurred with any study medication. The distribution to interstitial fluids and reliable tissue penetration are fundamental principles of successful antibacterial therapy of skin and skin-structure infections. The excellent tissue and interstitial fluid penetration of cefadroxil may contribute to its high degree of efficacy when administered once daily.
Tan J S; Salstrom S J M; File T M
Advances in Therapy
1994
1994-05
Journal Article
n/a
Serum Folate: A Pharmacodynamic Biomarker of Intracellular Nitrosylcobalamin Activity Following Intravenous Administration in Dogs
apo2l/trail; biomarker; cells; cobalamin; disease; dogs; Folate; homocysteine; methylmalonic acid; nitric-oxide; Nitrosylcobalamin; Oncology; pharmacokinetics; supplementation; suppression; vitamin B-12; vitamin B-12
Background/Aim: Cobalamin and folate are interdependent co-factors of the methionine synthase pathway. This study evaluated the effect of intravenously-administered nitrosylcobalamin (NO-Cbl), a vitamin B12 analog, on serum folate concentrations in healthy dogs. Materials and Methods: Four dogs received a 10-mg/kg, 20-mg/kg and 40-mg/kg intravenous bolus dose of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and post-dosing, and serum cobalamin and folate concentrations were measured. Results: For each dose, serum cobalamin concentrations were inversely correlated with serum folate concentrations. Spearman rank correlation coefficient values were -0.976 (10 mg/kg, p<0.0096), and -1.0 (20 mg/kg, p<0.008; 40 mg/kg, p<0.0046). Conclusion: Cellular uptake of NO-Cbl, following intravenous administration exerted a biological effect on folate similar to that previously described for other vitamin B12 analogs. Serum folate concentration may serve as a pharmacodynamic biomarker of intracellular nitrosylcobalamin activity following intravenous administration.
Sysel A M; Horne W I; Steiner J M; Suchodolski J S; Bauer J A
Anticancer Research
2012
2012-10
Journal Article
n/a
Pharmacokinetics of Intravenous Nitrosylcobalamin, an Antitumor Agent, in Healthy Beagle Dogs: A Pilot Study
apo2l/trail; canine organs; cobalamin; cobalamin vitamin-b-12; dogs; intravenous; nitric-oxide; Nitrosylcobalamin; Oncology; pharmacokinetics; protein; release; suppression; transcobalamin-ii; transport; vitamin B-12
Background/Aim: Nitrosylcobalamin (NO-Cbl) is a cobalamin-based anti-tumor agent. This study evaluated the pharmacokinetic parameters of NO-Cbl following intravenous administration in dogs. Materials and Methods: Four dogs received 10 mg/kg, 20 mg/kg and 40 mg/kg intravenous bolus doses of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and post-dosing, and noncompartmental pharmacokinetic parameters were determined. Results: Average peak serum concentrations of 2265, 5523 and 13,866 pg/mL were achieved following single-dose bolus intravenous administration of 10 mg/kg, 20 mg/kg and 40 mg/kg of NO-Cbl respectively. The average area under the curve was 12,697 h x pg/mL, 24,497 h x pg/mL and 44,976 h x pg/mL respectively, with an average elimination half-life of 16.2 h, 13.5 h and 13.1 h respectively. Conclusion: These results can be used to determine the dose and dosing intervals for clinical trials evaluating NO-Cbl in humans and companion animals.
Sysel A M; Horne W I; Steiner J M; Suchodolski J S; Bauer J A
Anticancer Research
2012
2012-09
Journal Article
n/a
Persistently positive culture results in a patient with community-acquired pneumonia due to Legionella pneumophila
azithromycin; clarithromycin; erythromycin; hospitalized-patients; Immunology; Infectious Diseases; legionnaires-disease; macrolides; Microbiology; pcr; pharmacokinetics; time
We describe a patient with community-acquired pneumonia due to Legionella pneumophila serogroup 6. This patient was found to have bronchoalveolar carcinoma of the lung by means of cytologic testing in 1 of 2 bronchoalveolar lavage samples, but no lesions were visible on bronchoscopy. Despite intravenous administration of azithromycin to the patient, repeat culture and polymerase chain reaction showed persistence of Legionella; the isolates remained susceptible to azithromycin. The patient did not respond to 14 doses of daily intravenously administered azithromycin. The poor outcome may have been partially due to the suspected underlying lung malignancy, as shown by cytologic examination, and by a delay in seeking medical attention.
Tan J S; File T M; DiPersio J R; DiPersio L P; Hamor R; Saravolatz L D; Stout J E
Clinical Infectious Diseases
2001
2001-06
Journal Article
<a href="http://doi.org/10.1086/320526" target="_blank" rel="noreferrer noopener">10.1086/320526</a>
Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis
drugs; efficacy; gold; low-dose methotrexate; ocular safety; pharmacokinetics; placebo; plasma; Rheumatology; serum concentrations; trial
Objective. A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug. Methods. Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. Results. The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. Conclusion. There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.
Munster T; Gibbs J P; Shen D; Baethge B A; Botstein G R; Caldwell J; Dietz F; Ettlinger R; Golden H E; Lindsley H; McLaughlin G E; Moreland L W; Roberts W N; Rooney T W; Rothschild B; Sack M; Sebba A I; Weisman M; Welch K E; Yocum D; Furst D E
Arthritis and Rheumatism
2002
2002-06
Journal Article
<a href="http://doi.org/10.1002/art.10307" target="_blank" rel="noreferrer noopener">10.1002/art.10307</a>
Antibiotic Dosing in Sustained Low-Efficiency Dialysis in Critically Ill Patients.
antibiotics; extended daily dialysis; pharmacokinetics; SLED; sustained low-efficiency dialysis
Purpose of review: Sustained low-efficiency dialysis (SLED) is increasingly used as a renal replacement modality in critically ill patients with acute kidney injury (AKI) and hemodynamic instability. There is, therefore, a greater need for the understanding of the antibiotic dosage and pharmacokinetics in these patients, to provide them with optimal therapy. Sources of information: PubMed/Medline, Embase, and Google Scholar. Methods: PubMed/Medline, Embase, and Google Scholar databases were searched using a combination of key words: dialysis, end stage renal disease, renal failure, sustained low efficiency dialysis, extended daily dialysis, prolonged intermittent renal replacement therapy (PIRRT), and antibiotic dosing. Studies that investigated antibiotic dosing and pharmacokinetics during SLED/extended daily dialysis/PIRRT were selected for this review. Key findings: Eleven studies met inclusion criteria and selected for data extraction. The data with regard to dialysis specifications, type of antibiotic including dosages, drug clearances, and dosage recommendations are summarized in Table 1. It is a challenge to find therapeutic doses for antibiotics during SLED therapy because, in general, only aminoglycosides and vancomycin can be assayed in clinical laboratories. Limitations: Although current studies on antibiotic dosing in SLED are limited due to diverse and undersized patient populations, antibiotic dosage adjustments for patients receiving SLED discussed here will serve as a valuable guide. Future large-scale research should focus on establishing guidelines for antibiotic dosage in SLED. Implications: Pharmacokinetic principles should be taken into consideration for the appropriate dosing of drugs during SLED, yet it is vital to monitor response to drug to make sure therapeutic goals are achieved. Antibiotic dosing and timing relative to the initiation of SLED may be important to maximize either the time above the minimum inhibitory concentration (MIC) (time-dependent) or the peak to MIC ratio (concentration-dependent), balancing efficacy and toxicity concerns. Critical care physicians should liaise with nephrologists to make decisions regarding appropriate antibiotic dosing in patients undergoing SLED.
Sethi Sidharth Kumar; Krishnappa Vinod; Nangethu Nisha; Nemer Paul; Frazee Lawrence A; Raina Rupesh
Canadian journal of kidney health and disease
2018
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1177/2054358118792229" target="_blank" rel="noreferrer noopener">10.1177/2054358118792229</a>