Search

Background: With rising resistance to terbinafine, and consistently high MICs to fluconazole and griseofulvin, itraconazole is being increasingly used as a first line drug for tinea corporis/cruris. However, inadequate clinical responses are often seen with it in spite of in vitro susceptibility. This is possibly related to a variable pharmacokinetic profile of itraconazole. The drug serum levels associated with the therapeutic outcome have not been defined in dermatophytic infections., Methods: Forty treatment naïve patients with tinea corporis/cruris were randomised to one of the three dose groups (100, 200 and 400 mg/day) of itraconazole. The drug serum levels of 21 of these patients were obtained after 2 weeks of treatment and correlated with the final clinical outcome and in vitro antifungal susceptibility data., Results: Trichophyton indotineae was identified by sequencing of ITS region of rDNA and TEF1α. All isolates were sensitive to itraconazole (Minimum Inhibitory Concentration (MICs) range: 0.06-0.5 µg/ml), while MICs to terbinafine were uniformly high (range 8-32 µg/ml). Thirty-seven patients (92.5%) achieved complete cure, while three failed treatment. Serum levels achieved with 400 mg/day were significantly higher than levels with 100 or 200 mg dose. All patients with itraconazole serum levels of >0.2 µg/ml were cured, while two out of the 10 patients with serum levels <0.2 µg/ml failed treatment., Conclusions: Therapeutic failures are uncommon with itraconazole, and the prevalent strain in India has low itraconazole MICs. Treatment failure is likely with itraconazole serum levels of <0.2 µg/ml, while levels >0.2 µg/ml are consistently associated with a positive therapeutic outcome., (© 2021 Wiley-VCH GmbH.)

Achievement of therapeutic drug levels appears to be mandatory when antifungal agents are used for the treatment of manifest mycoses. Based on the marked interindividual variability of trough levels, Therapeutic Drug Monitoring is of increasing concern during treatment with itraconazole, voriconazole or posaconazole. In addition, a broad spectrum of potential drug interactions has to be kept in mind during triazole treatment. In contrast, echinocandins reveal a more comfortable class of antifungal agents in this regard with no obvious incidence of nephrotoxic side effects compared to amphotericin B and its lipid formulations.

In the present study, the authors administered 100 mg itraconazole (ITCZ) twice daily for a period of 1 week to six patients with hyperkeratotic type tinea pedis, and examined its efficacy, safety profile, and usefulness. ITCZ concentration in stratum corneum was also measured to examine the mobility of the drug into the affected site of planta pedis. ITCZ concentration in the stratum corneum of the affected part was first detected at 1 week after the completion of administration, gradually increased over time, and peaked at 3 weeks, with the sum of ITCZ and hydroxyitraconazole (OH-ITCZ) amounting to 163.7 ng g(-1) on a average. It then gradually decreased to a total sum of 10.3 ng g(-1) on average at 8 weeks following the completion of administration. When compared with the geometric mean minimum inhibitory concentration (MIC) of ITCZ against fresh clinical isolates of dermatophytes (Trichophyton rubrum) (0.06 microg ml(-1)), the stratum corneum ITCZ concentration in this study was 2.1-fold of the geometric mean MIC at 2 weeks following the completion of administration, and 2.4-fold at 4 weeks. Although ITCZ does not produce therapeutic effectiveness (fungistasis) during the period of administration, it starts appearing at 2 weeks after the completion of administration, and after it peaks out at 3-4 weeks, clinical symptoms started improving. These results suggest that satisfying effects can be achieved in a short-term oral ITCZ at a dose of 100 mg twice daily for a period of 1 week in cases of hyperkeratotic type tinea pedis.

Invasive aspergillosis is an increasing cause of morbidity and mortality in immunocompromised patients. Extension of invasive aspergillosis to the central nervous system (CNS) is associated with an exceeding high mortality which approaches 100%. One major factor contributing to this devastating outcome is a poor penetration into the CNS of frequently used antifungal drugs, such as amphotericin B or itraconazole. Voriconazole, a new triazole with broad activity against various fungi, including Aspergillus species, shows superior activity in invasive aspergillosis compared to treatment with conventional amphotericin B. Voriconazole readily penetrates the blood-brain barrier yielding fungicidal drug concentrations within the CNS. A growing number of patients with CNS aspergillosis has been successfully treated with voriconazole in recent years. The pharmacological properties, the broad antifungal activity and the promising clinical data suggest that the use of voriconazole in CNS aspergillosis might improve the outcome in this otherwise devastating clinical condition. However, additional clinical data are needed to determine more precisely the role of voriconazole in CNS aspergillosis. In this review, we have compiled the available pharmacological and clinical data on CNS aspergillosis.

Itraconazole has become an important option in the management of invasive aspergillosis. The compound has potent and broad spectrum antifungal activity in vitro against Aspergillus spp. with a species- and strain dependent fungicidal mode of action. In vivo, the antifungal efficacy of itraconazole has been demonstrated in several non-immunocompromised and immunocompromised animal models of disseminated and invasive pulmonary aspergillosis. Itraconazole is available in oral and intravenous formulations, displays non-linear plasma pharmacokinetics, and is usually well tolerated. Non-comparative clinical data of itraconazole for therapy of suspected or proven invasive aspergillosis suggest response rates similar to those of conventional amphotericin B; however, the experience with itraconazole for induction therapy of invasive aspergillosis is limited, particularly in profoundly neutropenic patients. Itraconazole has an important role for consolidation and maintenance therapy of patients with invasive aspergillosis, and novel combination therapies involving itraconazole are currently under intensive preclinical investigation as to their usefulness for primary therapy.

Itraconazole distribution is largely dependent on its high liposolubility. Intrapulmonary lung concentrations remain unknown in haematological patients. We report itraconazole lung concentrations in such patients treated with itraconazole. Itraconazole and hydroxyitraconazole were measured by high-performance liquid chromatography in concomitant blood samples and lung post-mortem biopsies (three cases) or lung lobectomy (one case). These itraconazole and metabolite lung concentrations were sufficient to be active on Aspergillus.

A clinical study was carried out in 19 patients with onychomycosis in whom itraconazole was orally administered in a single daily dose of 100 mg. A follow-up period was instituted subsequent to the administration period to that the course of the nail lesions could be monitored. The concentrations of the drug in the plasma and in the nails were also determined. In patients in whom itraconazole was administered for 12-16 weeks, the decrease in the turbidity and thickening of the nails was maintained even after the administration period was completed. The efficacy rating in the overall evaluation at 12 weeks was 84.2% (16/19). In the evaluation performed at 24 weeks, the rating was 94.7% (18/19). These data indicate that the effect of itraconazole was maintained even after completion of the administration period. The retention of the drug in the nail after completion of the administration period was investigated in terms of the mean concentration of the drug in the nail with the passage of time in patients administered itraconazole for 10-16 weeks. It was found that a certain level of itraconazole was retained in the nail until at least the 24th week. Adverse reactions seen in this study consisted of diarrhoea and drug eruption, one case cach, and elevations of glutamic oxaloacetic transaminase and glutamic pyruvic transminase in one case.

In this study we have investigated the influence of keratin on the efficacy and pharmacokinetics of fluconazole and additional azole antifungal agents. It is well known that the penetration and distribution of oral antifungals is strongly influenced by plasma protein binding. Especially, itraconazole and ketoconazole show a high binding affinity to plasma proteins, whereas fluconazole binds only with 12%. All of these antifungals, however, are accumulated in the stratum corneum of the skin. These observations have stimulated interest, if structure proteins of the skin like keratin interact with antifungals may explain of the accumulation process. Therefore we have measured the binding kinetics between keratin and the azoles. Keratin from sheep wool was degreased, purified and incubated with azole antifungals. After defined incubation periods the azoles were extracted and assayed by thin layer chromatography following UV-detection. There was a specific binding between keratin and all of the used substances. Interestingly, the binding affinity of fluconazole to keratin was much higher than to plasma proteins. Thus our observations indicate that the accumulation in the stratum corneum is a consequence of the interaction between keratin and azole derivatives.

Forty AIDS patients suffering from fluconazole-resistant oropharyngeal candidosis were treated with oral itraconazole solution (200-800 mg/day). In 39/49 patients the disease could be initially cured or significantly improved. In contrast to the good clinical results, however, only in six patients a yeast count reduction was observed, and in four patients unchanged high yeast counts persisted. The main pathogen was C. albicans. Even in longtime treatment itraconazole solution was well tolerated. In two patients only the therapy had to be stopped due to the increase of transaminases. Considerable individual deviations in serum concentrations of itraconazole or hydroxy-itraconazole, respectively, were observed which correlated only to a minor degree with clinical and mycological results. Application of itraconazole in a soluble preparation caused an increase in efficacy due to simultaneous local and systemic action. In the case of resistance to fluconazole the itraconazole solution is a valuable alternative to the administration of amphotericin B which is rich in adverse reactions.

Itraconazole possesses nonlinear pharmacokinetics. We used the Michaelis-Menten model for calculating dosing rates under steady-state conditions. We determined a Michaelis-Menten constant of about 0.3 micrograms/ml from the data of two publications and from our own investigations. From the steady-state concentrations we calculated the necessary amount for the realization of a desired concentration of 1.0 micrograms/ml. The interindividual differences and intraindividual changes of the pharmacokinetics were high (median: 6.9 mg/kg/d (2.7-17.1), n = 110). The intraindividual stability of the pharmacokinetics of repeatedly investigated patients (n = 20, individual time of observation: 4 to 296 days, median: 30 d) depended on various pathophysiological factors of influence. The individual duration of pharmacokinetically stable periods in relation to the respective observation time ranged between 0 and 100% (median: 75%, n = 23). In the initial days of treatment the course of itraconazole concentrations in repeatedly investigated patients (n = 6) was not uniform. Under constant dosage only one patient showed the increase in concentrations described in the literature during the first week of treatment. In this period of treatment probably three pharmacokinetic processes overlap one another: the establishment of the steady state, and systematic changes as well as changes caused by pathophysiological factors of the underlying disease. The development of therapeutic drug monitoring (with the calculation of the needed dosages) was unproblematic with the use of standard procedures. Necessity and frequency of therapeutic drug monitoring depend on the accepted ranges of concentration during long-term therapy, on the expected deviation of the pharmacokinetics during the course of the basic illness of the individual patient and on potential drug interactions.

Itraconazole is a lipophilic triazole antifungal with a broad spectrum of activity. Most of the important fungal pathogens respond to itraconazole concentrations of 100 ng/ml. Therefore, itraconazole is suitable for treatment of a variety of systemic mycoses, as aspergillosis, cryptococcosis, candidosis as well as non-European endemic mycoses. The lipophilicity of the molecule is the reason for a pronounced tissue affinity meaning that the tissue levels of the drug usually are substantially higher than the corresponding plasma levels. This fact has to be kept in mind when plasma measurements are being used to decide a therapeutic approach for a systemic fungal infection. In contrast to the skin, internal organs will not show a long term retention of itraconazole in the tissues. This means that for systemic mycoses the therapy needs to be continued until clinical and mycological cure is obtained. Reduced itraconazole absorption may occur in a minority of patients because of underlying chemotherapy or dramatic changes in stomach pH. This is occasionally seen in patients with allogeneic bone marrow transplants and end-stage AIDS patients. Use of antacida and H2-antagonists somewhat reduces the absorption of itraconazole, however, often not in a clinically meaningful way. Itraconazole increases the levels of cyclosporin A. Itraconazole levels are decreased by rifampicin, phenytoin and phenobarbital. Caution is required in patients on concomitant anticoagulants.