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Candida and parasitic infection: Helminths, trichomoniasis, lice, scabies, and malaria
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Treatment of Candida vulvovaginitis in pregnancy is typically limited to topical azoles and nystatin (16,25). For many years, nystatin was the primary drug used for Candida vulvovaginitis in pregnancy because its extremely poor absorption was felt to improve its safety (pregnancy category B) (25). As studies have proven, the increased efficacy of the azole antifungal agents, miconazole, clotrimazole, butoconazole, and terconazole, has become the mainstays of therapy in pregnancy. They have been used extensively in human pregnancy with no adverse effects or increase in congenital malformations noted, but most remain pregnancy category C due to the absence of adequate controlled human studies. There is no clear leader from this group in terms of efficacy and patient satisfaction, so selection may be based on availability and cost. Seven-day treatment is usually needed in pregnancy due to the higher rates of treatment failure and recurrence. Cure rates are typically 5% to 10% lower than those in nonpregnant women for the same dosing regimen.
Novel and emerging pharmacotherapy and device-based treatments for onychomycosis
Published in Robert Baran, Dimitris Rigopoulos, Chander Grover, Eckart Haneke, Nail Therapies, 2021
Jose W. Ricardo, Shari R. Lipner
VT-1161 is a novel tetrazole CYP51 inhibitor designed to selectively target fungal enzymes and maintains high potency for the fungal target with low levels of interaction with human CYPs. This may translate to a more favorable side effect profile compared to other azoles. In vitro and in vivo studies have demonstrated broad-spectrum activity against both Candida species and dermatophytes. In a randomized, phase 2b study, with a daily dosing regimen of 300 mg or 600 mg for 14 days, followed by a once-weekly dose (same strength) for either 10 weeks or 22 weeks, mycological cure was achieved for 61% to 72% of patients at week 48, whereas complete cure rates ranged from 32% to 42%.
History of antifungals
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Emily L. Larkin, Ali Abdul Lattif Ali, Kim Swindell
Azoles inhibit the synthesis of ergosterol, the major sterol in the fungal cell membrane, via inhibition of the cytochrome P450 enzyme, lanosterol demethylase [41,42]. This inhibition results in disruption of cell membrane integrity with eventual death.
Risk of fetal malformation, spontaneous abortion, and adverse pregnancy outcomes after gestational terbinafine exposure: a systematic review
Published in Journal of Dermatological Treatment, 2022
Philipp Foessleitner, Alex Farr, Julia Deinsberger
When a fungal infection is diagnosed during pregnancy, it is important to identify the appropriate antifungal treatment. Topical azoles, including fluconazole, itraconazole, and clotrimazole, are recommended as first-line therapy during pregnancy (21–23). In cases of severe symptoms, recurrence, or when topical therapy fails, oral azoles are recommended in non-pregnant patients (21). However, the safety of oral azoles during pregnancy is controversial. Recent meta-analyses regarding this topic found an increased likelihood of heart and limb malformations and spontaneous abortion after gestational exposure to oral fluconazole (24,25). Additionally, oral itraconazole use during pregnancy was associated with an increased risk of eye defects (25). Furthermore, these agents have the ability to disrupt estrogen and testosterone synthesis, although it remains unclear if fetal corticosteroid synthesis is affected (10). Griseofulvin, another antifungal agent was shown be have teratogenic effects in animals; however, data on humans are limited (26). In light of these findings, terbinafine could offer a safe alternative as antifungal treatment during gestation.
Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens, and clinical considerations
Published in Expert Review of Clinical Pharmacology, 2021
Maria Siddiqui, Marina Konopleva
As venetoclax is metabolized by the CYP3A4/5 system doses need to be adjusted with concomitant use of other drugs [108]. These are most relevant given common utilization of azoles for antifungal prophylaxis or therapy of invasive fungal infections. In a study by Agarwal et al., pharmacokinetics of venetoclax monotherapy and in combination with 300 mg of posaconazole were studied. Patients received decitabine days 1–5 days during which venetoclax was ramped up from 20 to 200 mg which was continued till day 20. The patients were then divided into three groups with venetoclax monotherapy 400 mg, venetoclax 50 mg with posaconazole, and venetoclax 100 mg with posaconazole. On day 21, the posaconazole groups received 600 mg in addition to respective venetoclax dosing and from D22-28, 300 mg posaconazole was used. Samples for pharmacokinetic assessment were drawn on D20 and D28. The mean drug concentration was 2.34 mg/mL vs 2.78 mg/mL vs 3.74 mg/mL for venetoclax monotherapy, 50 mg and 100 mg venetoclax in combination with posaconazole. The measured exposure of venetoclax on day 28 showed higher levels in the combination groups as opposed to monotherapy. Consequently, D20 and D28 levels of venetoclax monotherapy vs co-administration of 50 mg and 100 mg venetoclax with posaconazole showed an increase in the bioavailability of 76% and 155% and Cmax by 53% and 93%. Based on these studies, venetoclax dose reduction by at least 75% when co-administered with posaconazole [119]. Common dosage adjustments are presented in Table 3.
Azole resistance in Aspergillus species: promising therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Shirisha Pasula, Pranatharthi H. Chandrasekar
Use of high dose azoles in the treatment of azole-resistant Aspergillus infection is still unclear. Posaconazole has been considered for oral step-down treatment of azole-resistant invasive aspergillosis as the MICs of posaconazole vs azole-resistant A. fumigatus are generally close to the resistance breakpoint suggesting that patients may respond if the drug exposure is increased [48,49]. For posaconazole suspension, a dose escalation is not recommended because of its limited absorption [50]. For the successful treatment of Aspergillus with posaconazole MICs of 0.5 mg/l, therapeutic concentrations should achieve >3.3 mg/l; posaconazole tablets and intravenous formulations are favorable in reaching sufficient drug levels [49,50]. Pharmacokinetic and target attainment simulation model study showed that high dose isavuconazole treatment might be an option in patients infected with a wild type A. fumigatus isolate with an isavuconazole MIC of 2 mg/L. However, high-dose azole treatment requires caution owing to possible toxicity and drug interactions and would require intensive therapeutic drug monitoring [51]. Further research is needed to investigate efficacy and safety of using azoles in azole-resistant Aspergillus infections, and at present, it is best to avoid azole use in such situations.