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Antifungal agents with broad-spectrum activity

Antifungal agents with broad-spectrum activity

Broadd-spectrumamphotericin B, or brosd-spectrum therapy of experimental murine cerebral phaeohyphomycosis due to Ramichloridium obovoideum "Ramichloridium mackenzei". A series of reports has activkty the pharmacokinetic exposure of CLA for post-workout recovery Glycogen replenishment during high-intensity training relative CLA for post-workout recovery the MIC of the infecting pathogen as a means of optimizing treatment efficacy. Absorption is not affected by food consumption, gastric pH, or disease state [ 3839 ]. Amphotericin B and griseofulvin remained the only systemic therapeutic options for invasive fungal disease until the early s, when flucytosine Ancobon; Valeant Pharmaceuticals was released. AMB formulations are commonly used to treat fungal infections.

Antifungal agents with broad-spectrum activity -

Today, each member of the azole class can be administered orally; however, the degree of absorption and optimal administration conditions vary for each of these drugs table 2. Differences can even exist between various formulations of the same agent. Absorption is not affected by food consumption, gastric pH, or disease state [ 38 , 39 ].

Variable gastrointestinal absorption does occur with the other members of this class, however, and, for one compound itraconazole , it varies according to the specific formulation.

Oral bioavailability of these agents can be also be affected by food consumption and changes in gastric pH. Itraconazole capsules demonstrate optimal absorption in the presence of gastric acid and, therefore, cannot be coadministered with agents known to raise gastric pH, such as H 2 receptor antagonists or proton pump inhibitors [ 72 , 73 ].

Furthermore, itraconazole capsules should be administered after a full meal to optimize absorption [ 74 ]. In general, the cyclodextrin solution is more efficiently absorbed i. In addition, antacid therapy does not have a negative effect on absorption [ 41 , 75 ].

Food can decrease serum concentrations of itraconazole solution; therefore, this preparation should be administered on an empty stomach [ 42 , 43 ]. Thus, this agent should be administered on an empty stomach. In contrast, posaconazole absorption is optimized when administered with a high-fat meal or a similar composition nutritional supplement, such as Boost Plus Novartis Nutrition [ 46 ].

The distribution of antifungal agents in the body is another important factor to consider in the treatment of invasive fungal infections, because these infections may occur at physiologically sequestered sites.

As demonstrated by relatively large volumes of distribution, the available antifungal agents are widely distributed throughout the body, with a few significant exceptions discussed below [ 37 , 41 , 45 , 47 , 48 ]. The main factors affecting drug distribution are molecular size, charge, degree of protein binding, and route of elimination.

Fungal infections of the CNS are associated with high morbidity and mortality and are difficult to treat. Many antifungal agents have large molecular weights that preclude their ability to penetrate the blood-brain barrier and achieve therapeutic CSF concentrations.

The concept of CSF concentrations predicting the efficacy of antifungal agents for CNS infections is a bit misleading. For example, amphotericin B, a drug that is essentially undetectable in CSF, has been the mainstay of treatment for cryptococcal meningitis, despite the lack of detectable drug concentrations in the CSF [ 31 , 78 ].

In these instances, it is postulated that tissue concentrations of these agents are adequate to allow efficacy. Recent investigations have suggested that brain parenchymal concentrations of the azole agents and echinocandins may be more meaningful for prediction of therapeutic response.

Ophthalmologic fungal infections are also difficult to treat. Traditionally, topical therapies have been used for these infections, especially when the disease is limited to superficial infection.

Many of the available systemic antifungal therapies can achieve intraocular concentrations adequate for treatment of more invasive disease table 2. For other agents, localized therapy, such as intravitreal injections, is required for reliable concentrations within the vitreous body.

Relatively few available antifungal agents are renally eliminated as unchanged drug or active metabolite and, therefore, do not provide high concentrations of microbiologically active drug in the urine table 2. It is important to note that, because many of these agents produce adequate tissue concentrations, a lack of detectable urine concentrations does not necessarily preclude use when the disease involves renal parenchyma.

The degree of protein binding is another characteristic that alters systemic exposure to drug; a protein-bound drug is not available for microbiologic activity.

Thus, this factor plays an important role in determining the amount of active drug present at a given site of infection [ 79 ]. Unfortunately, the majority of available pharmacokinetic data for the antifungal agents reflect concentrations of total drug.

Therefore, clinicians are left to hypothesize about the amount of measured drug actually available to fight infection i. The major protein that binds these drugs is albumin, although other serum proteins may also play a role [ 82 , 83 ]. Many patients who are at risk for fungal infection are malnourished and, as a result, have low levels of serum albumin.

The effect of this on protein binding of drugs may result in higher concentrations of available or active drug; however, this concept has not been sufficiently studied with regard to a potential effect on antifungal drug dosing or efficacy [ 79 , 84—86 ].

Metabolism and elimination. Many systemic antifungal agents undergo some degree of hepatic metabolism before elimination. For the amphotericin B products, the exact routes of metabolism and elimination are largely unknown [ 4 ]. All azole antifungals undergo some degree of hepatic metabolism table 2.

For fluconazole, the role of metabolism in drug elimination is minimal, but this is not the case with itraconazole, voriconazole, and posaconazole, which are highly dependent on metabolism for drug elimination. Given that there are few active antifungal metabolites, this results in production of inactive compounds that provide no clinically meaningful activity, with the notable exception of hydroxyitraconazole a metabolite of itraconazole [ 87 ].

Although oxidative metabolism is the primary process involved in azole metabolism, glucuronide conjugation does occur with some of these drugs, especially posaconazole [ 88 ]. Each of the 2 available echinocandins caspofungin and micafungin undergoes metabolism to produce 2 distinct inactive metabolites.

For caspofungin, these processes are hepatic hydrolysis and N -acetylation [ 89 ]. Micafungin undergoes nonoxidative metabolism to produce 2 distinct compounds [ 90 ]. Although it is a weak substrate for cytochrome P CYP , the metabolism of micafungin does not appear to be affected by inhibitors or substrates of this enzyme system.

Unlike caspofungin and micafungin, anidulafungin is not hepatically metabolized but undergoes nonenzymatic degradation [ 91 ]. Effect of organ dysfunction on drug dosing.

The effect of organ dysfunction on the elimination of the antifungal agents is summarized in table 3.

Although the various formulations of amphotericin B are known for their ability to cause nephrotoxicity, they do not require dose adjustment for patients with decreased renal function. In fact, of all the available systemic antifungal agents, only fluconazole and flucytosine require dosing modification when given to patients with decreased levels of creatinine clearance [ 4 , 48 ].

In some instances, such as with amphotericin B, dosing regimens may be altered in attempts to ameliorate toxicity, but this is not done as a result of altered drug clearance. Another example is the cyclodextrins, which are present in the intravenous preparations of itraconazole and voriconazole and can accumulate in renal disease.

Suggested dose modifications for antifungal agents, by type of organ dysfunction. Hepatic disease can also affect the elimination of several antifungal agents.

For the majority of these agents, however, no dose alteration is recommended. Of the azoles, only voriconazole requires dose reduction for patients with mild-to-moderate cirrhosis [ 45 ].

Similarly, caspofungin is the only echinocandin with recommendations for dose modification in severe hepatic disease [ 47 ]. The metric used to determine appropriate dosing in hepatic disease is the Child-Pugh scoring system, which is appropriate for patients with chronic liver dysfunction but not for patients who have acute hepatic injury.

Currently, information is not available to guide drug dosing in this clinical scenario. Drug-drug interactions. The effect of antifungal agents on other therapeutic regimens merits serious consideration when therapy is being initiated or discontinued. Antifungal drugs can alter the safety or efficacy of concomitant therapies through several mechanisms.

The first of these involves additive toxicities associated with concomitant administration; the most apparent example is nephrotoxicity caused by amphotericin B. This toxicity can enhance the renal effect of many other agents, including cyclosporine and the aminoglycosides [ 93 ].

A more complicated issue relates to the inhibition of drug metabolism that occurs as a result of these drug interactions.

A complete review of CYPmediated drug interactions is beyond the scope of this article, but the importance of this effect should not be minimized [ 94 ]. Because of their mechanism of action, all the azole antifungals inhibit CYP enzymes to some degree table 4.

As a result, careful consideration must be given when an azole agent is added to a patient's drug regimen. Similarly, when an azole agent is discontinued, the change in metabolism that occurs may have profound clinical implications.

For example, organ rejection has been reported after discontinuation of an azole antifungal that was not accompanied by the necessary upward dose adjustments in the affected immunosuppressant agent e.

Summary of azole-mediated cytochrome P drug-drug interactions. Although caspofungin and micafungin are not major substrates for the CYP enzyme system, they both have interactions that appear to be mediated via this mechanism.

Caspofungin concentrations are decreased when administered with CYP inducers, such as rifampin and phenytoin [ 98 ]. Micafungin does have weak inhibitory properties against CYP3A4 and has been shown to increase serum concentrations of substrates of this enzyme.

This phenomenon has been specifically assessed with sirolimus and nifedipine, and, in both cases, the AUC of the target drug was significantly elevated [ 54 ].

Anidulafungin does not appear to exhibit these CYPmediated interactions [ 91 ]. Initial product labeling for caspofungin indicated that a drug-drug interaction occurred when this agent was administered in combination with cyclosporine.

This was based on data obtained in studies of healthy volunteers who received these drugs in combination as part of phase 1 development of caspofungin.

After coadministration, an unacceptable elevation in hepatic enzymes was seen; therefore, cyclosporine was prohibited in clinical trials of caspofungin.

This prohibition was reflected in the warning section of the initial caspofungin package insert [ 47 ]. More recent data, however, suggest that this effect is not reproducible in infected patients receiving the drug [ 99 , ]. In consideration of these data, these warnings have recently been revised in the product labeling.

Another mechanism involved in drug-drug interactions relates to the role of P-glycoprotein P-gp. P-gp is a transporter protein involved in the absorption and distribution of drugs, as well as drug resistance. In a fashion similar to their interactions via the CYP enzyme system, azole antifungals have affinity for P-gp, because of their mechanism of action at the fungal cell membrane.

More specifically, itraconazole is both a substrate and an inhibitor of P-gp, whereas fluconazole does not inhibit P-gp but may be a weak substrate. Therefore, interactions among the azole antifungals with P-gp may affect response to therapy or may play a role in interactions with other medications [ ].

Another important consideration in the optimization of antifungal treatment regimens is the interaction between the fungal pathogen, the antifungal agent, and host factors.

These pharmacodynamic principles have not been described for antifungal agents with the same level of detail as for the antibacterial agents. However, fairly extensive in vitro and animal model investigations have been undertaken with agents from the triazole, polyene, and echinocandin antifungal classes.

A series of reports has defined the pharmacokinetic exposure of these compounds relative to the MIC of the infecting pathogen as a means of optimizing treatment efficacy. In animal models of disseminated candidiasis, killing of fungal organisms with echinocandins and polyenes is optimized by achieving peak drug concentrations 2—fold in excess of the MIC [ , ].

Treatment outcome with the triazole antifungals has been shown to correlate with the drug exposure over time, which is similar to the concentration needed to inhibit the organism in vitro, or the MIC.

The pharmacokinetic index that best accounts for the entire exposure over time is the ratio of the h AUC to the MIC h AUC : MIC.

In preclinical infection models, a free drug h AUC : MIC value near 25 : 1 has been shown to reproducibly predict outcome with each of the triazole compounds [ ].

Examination of clinical trial data with Candida infections has suggested that this pharmacodynamic relationship is similarly helpful for prediction of treatment efficacy in humans [ , ].

The clinical relevance of the relationships between a specific drug exposure, the MIC, and outcome is less clear for other fungal pathogens and drug classes. The relationship between antifungal pharmacokinetics and certain host toxicities has been demonstrated for a few compounds.

Several decades ago, the relationship between flucytosine serum concentrations and bone marrow toxicity was elucidated [ ]. More recently, the toxicodynamic relationship between higher-than-anticipated voriconazole exposure and hepatoxicity has been suggested [ ]. More extensive evaluation of clinical data will be necessary to better understand these important pharmacodynamic relationships.

To aid clinicians in implementing these principles, serum drug concentration monitoring is now available for several of the available antifungal agents. Table 5 outlines the appropriate conditions for monitoring, target concentrations, and the association between this information and clinical outcomes, either therapeutic or toxic.

Table 6 reviews the major comparative toxicities of the systemic antifungal agents available for management of invasive fungal disease. In addition to the types of toxicities presented i. Amphotericin B preparations.

The toxicity of amphotericin B is well known. In addition to the nephrotoxicity and acute infusion-related reactions associated with the drug, a unique pulmonary reaction can be seen, particularly with certain lipid preparations.

With the liposomal preparation of amphotericin B, a triad of infusional toxicity has been characterized. This toxicity can manifest as a combination of the following clinical scenarios: pulmonary toxicity i. Similarly, with amphotericin B colloidal dispersion, severe hypoxia has been reported in patients; in one study, hypoxia occurred more commonly in association with the use of amphotericin B colloidal dispersion than with amphotericin B deoxycholate [ ].

Hypoxia has also been reported in association with use of the lipid complex of amphotericin B. Azole antifungal agents. Fluconazole is an extremely well-tolerated agent that lacks significant toxicity, despite having been used for treatment and prophylaxis in many patient populations for more than a decade.

However, reversible alopecia is not uncommon with this agent [ ]. Oral itraconazole solution is also relatively safe but can be associated with nausea and diarrhea severe enough to force discontinuation.

This reaction is caused by the excipient hydroxypropyl-β-cyclodextrin, which is used to increase solubility of the parent drug [ ].

Itraconazole has been described as causing a unique triad of hypertension, hypokalemia, and edema, mostly in older adults [ ]. A negative inotropic effect resulting in congestive heart failure has also been described and has prompted changes to the package labeling to avoid administration of itraconazole to patients with a history of heart failure [ 41 , ].

Two unique adverse events have been associated with the use of voriconazole: visual disturbances and cutaneous phototoxicity. The mechanism for visual disturbances is not known but manifests itself as photopsia i. This effect is usually mild and transient, and it abates with continued treatment.

In addition, this effect appears to be associated with higher doses of voriconazole [ ]. This effect is not prevented through the use of sunscreens but is reversible after discontinuation of therapy. Posaconazole has been well tolerated in clinical trials to date. The most frequently reported adverse events attributed to the drug have been associated with hepatic toxicities.

These toxicities seem to occur less frequently than with other members of the triazole class [ ]. Fatal hepatotoxicity has been reported with itraconazole, voriconazole, and posaconazole. Therefore, close monitoring of hepatic function is warranted with all members of the azole class [ 41 , 45 ].

The echinocandins are associated with few toxicities, making them safe agents to administer. The most notable, yet uncommon, event reported is a histamine-mediated infusion-related reaction.

As with vancomycin, this reaction can be relieved by slowing the rate of infusion or premedicating with an antihistamine, such as diphenhydramine. Clinicians now have access to an expanded number of antifungal agents; however, the panacea of antifungal therapy remains to be found.

Therefore, a keen appreciation of the properties associated with each antifungal agent is imperative in the selection and administration of antifungal therapy. Differences in the pharmacokinetics of each unique drug render effective administration a challenge, particularly given the complex regimens that patients who are at risk for fungal infection receive because of their underlying disease states.

Toxicity profiles also play a major role in the treatment of fungal disease, and differences among the antifungal classes, as well as agents within a given class, must be understood. With judicious use of the available agents, we are able to successfully and safely treat a growing number of life-threatening infections.

Nevertheless, important questions remain. Clinical studies of the echinocandins and posaconazole are underway to clarify their niche in the antifungal armamentarium.

The pharmacokinetics of the newer agents and their efficacy in paediatric populations also require clarification. Other areas that need to be addressed include whether the addition of cytokines to the newer agents improves outcomes, and how best to study, and translate into clinical use, antifungal drug combinations.

The answers to these and other questions will help define the future directions in antifungal therapy. Adverse effects Stevens—Johnson syndrome, hair loss, electrolyte disturbances eg, hypokalaemia , cardiovascular effects eg, QT c prolongation, arrythmias , hallucinations.

Oral: not required. Not required for acute hepatic injury; half maintenance dose in cirrhosis Child—Pugh A and B ; drug not recommended in severe cirrhosis Child—Pugh C. Increased plasma concentrations of other drug substrates. Increased proton-pump inhibitor levels, decreased triazole absorption.

Prevention of infusion-related toxicity §. Before therapy, a test dose is recommended to identify patients in whom severe infusion-related reactions might occur. Value of corticosteroids not proven. Usually requires oral azole itraconazole preferred or terbinafine E2.

Terbinafine preferred E1 or oral azole itraconazole E2. Topical nystatin or amphotericin B; systemic fluconazole in immunocompromised patients E2. Systemic fluconazole E2 ; echinocandin E2 or newer triazoles E2 if indicated.

All formulations creams, powders, troches available without prescription. Evidence of the statements made in this article is graded according to the National Health and Medical Research Council NHMRC system 32 for assessing the level of evidence:.

E1: Evidence obtained from a systematic review of all randomised controlled trials. E2: Evidence obtained from at least one properly designed randomised controlled trial.

E3 1 : Evidence obtained from well designed pseudo-randomised controlled trials alternate allocation or some other method.

E3 2 : Evidence obtained from comparative studies with concurrent controls and allocation not randomised cohort studies , case—control studies, or interrupted time series without a parallel control group.

E3 3 : Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4: Evidence obtained from case series, either post-test, or pre-test and post-test. AMB, FLU, CAS and VOR equally effective E2.

Lipid AMB formulations can also be considered if neutropenic E3 1. Tailor choice of agent to species of Candida and susceptibility result. Candidaemia: 14 days after last positive culture or after resolution of all symptoms and signs if neutropenic expert opinion.

Other invasive candidiasis: varies with site of infection. Initial therapy: AMB with or without flucytosine for central nervous system disease and if not neutropenic E2. Maintenance therapy: FLU E2 , or other triazole E4. Induction therapy: 2—6 weeks. Maintenance therapy: 3 months to 1—2 years; varies with host status and disease extent E2.

Initial therapy: VOR is treatment of choice E2. If patient is intolerant to VOR, lipid AMB is preferred over conventional AMB E2.

Maintenance therapy: VOR E2 ; POS E4. Salvage therapy: CAS E4. Until complete response evident, along with recovery of immune deficit.

Indefinite treatment if persistent immunosuppression expert opinion. Maintenance therapy: POS expert opinion. Initial therapy: VOR with or without terbinafine E4. Maintenance therapy: VOR E4. Initial therapy: AMB formulation E2. Maintenance therapy: ITC E2 ; FLU E4 , VOR E4 , POS E4 second line.

Sharon Chen and Tania Sorrell were chief investigators for the Australian Candidaemia Study on an educational grant from Pfizer Australia. Tania Sorrell has received untied grants from Merck, Sharpe and Dohme and Gilead Sciences and both have received travel assistance to attend meetings from Pfizer Australia, Gilead Sciences, Schering-Plough Australia, and Merck, Sharpe and Dohme.

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Article types. Research letters. Guidelines and statements. Narrative reviews. Ethics and law. Medical education. New Drugs, Old Drugs. Volume Issue 7. Sharon C A Chen and Tania C Sorrell. Med J Aust ; 7 : x Published online: 1 October facebook twitter linkedin email. Topics Infectious diseases.

Abstract The four main classes of antifungal drugs are the polyenes, azoles, allylamines and echinocandins. Classes of antifungal agents Most antifungal drugs interfere with biosynthesis or integrity of ergosterol, the major sterol in the fungal cell membrane.

Antifungal agents Azole antifungal agents These are the most widely used antifungal drugs, and act primarily by inhibiting the fungal cytochrome P enzyme, 14 α -demethylase.

Second generation triazole agents Voriconazole and posaconazole are second-generation triazoles with an extended spectrum of activity against yeasts, C. Adverse effects In general, the triazoles are relatively safe, even when used for prolonged periods. AMB formulations AMB formulations are commonly used to treat fungal infections.

AMB deoxycholate Conventional AMB or AMB deoxycholate has long been used to successfully treat various yeast, cryptococcal and mould infections.

Lipid preparations of AMB Two of three marketed lipid formulations of AMB are licensed in Australia: liposomal AMB and AMB lipid complex Box 3. Echinocandins There are three clinically important echinocandins. Terbinafine Topical and oral preparations of this allylamine drug are widely used to treat nail and skin infections, and terbinafine is the treatment of choice for onychomycosis Box 4.

Flucytosine Flucytosine should not be administered as a single agent because of rapid development of resistance. Superficial fungal infections Fungal infections of the skin level of evidence E3 1 or mucosa E2 can usually be successfully managed by topical imidazole preparations see Box 5 for level-of-evidence codes.

Invasive fungal infections Treatment of IFIs is usually initiated in hospitals, but is increasingly continued in the outpatient setting. Combination antifungal therapy The only fungal infection for which combination therapy is of proven clinical benefit is cryptococcocal meningitis where treatment with AMB formulations plus flucytosine results in higher cure rates and more rapid CSF sterilisation.

Adjunctive therapy Surgery may be required in instances such as fungal endocarditis or for large isolated lesions eg, pulmonary cryptococcomas that persist despite antifungal treatment E4.

The future The release of new antifungal agents with improved efficacy and safety profiles is good news for patients with both superficial and invasive fungal infections. Topical nystatin or amphotericin B; systemic fluconazole in immunocompromised patients E2 Oesophageal candidiasis Candida spp.

Mould infections Invasive aspergillosis Initial therapy: VOR is treatment of choice E2. Scedosporium infections Initial therapy: VOR with or without terbinafine E4. Infections caused by dimorphic fungi Initial therapy: AMB formulation E2. View this article on Wiley Online Library. Sharon C A Chen 1 Tania C Sorrell 2 Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, NSW.

Correspondence: sharonc icpmr. Competing interests:. Kauffman CA. New antifungal agents. Semin Respir Crit Care Med ; Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev ; Walsh TJ, Groll A, Hiemenez J, et al.

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J Clin Microbiol ; Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of blood stream infection due to Candida species and in vitro susceptibilities of isolates collected from to in a population-based active surveillance program. Marr KA, Carter RA, Crippa F, et al.

Epidemiology and outcome of mould infections in haematopoietic stem cell transplant recipients. Clin Infect Dis ; Lin S, Schranz J, Teutsch S. Aspergillosis case-fatality rate: systemic review of the literature.

Gudlaugsson O, Gillespie S, Lee K, et al. Attributable mortality of candidaemia, revisited. Ullmann AJ, Cornerly OA. Antifungal prophylaxis for invasive mycoses in high risk patients. For the most part, specific antifungal agents have replaced nonspecific topical treatments, such as keratolytics salicylic acid or antiseptics gentian violet or Castellani paint , which were once the cornerstones of management.

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Aspergillus niger, Vitamin C for collagen production fumigatus, Candida albicans, Cryptococcus neoformans, Tricophyton rubrum, Epidermophyton foccosum and Microsporum canis.

These compounds represent activkty novel class wigh metal-based antifungal agents which Antifungsl opportunities for a large number of synthetic variations for modulation Fueling for agility and speed before competition the activities.

Agentz CLA for post-workout recovery a preview agent subscription content, log in broaad-spectrum an institution to check access. Rent this article via Antifungal agents with broad-spectrum activity. Institutional subscriptions.

Collins FM, Klayman DL, Morrison NE Correlations broad-zpectrum structure and antimycobacterial Pycnogenol and osteoporosis prevention in a series of 2-acetylpyridine thiosemicarbazones.

J Gen Microb — Google Scholar. Cooper KE The theory of antibiotic inhibition zones. Actiivity Kavanagh F ed Analytical microbiology. Academic Press, New CLA for post-workout recovery, pp 1— Eisner Antifujgal, Eisner U Derivatives of hydroxylamine and hydrazine.

In: CLA for post-workout recovery AJ, Lund H eds Antifungsl of electrochemistry sctivity the elements. CLA for post-workout recovery Agsnts, New York, vol XII, Enhancing wellbeing with phytochemicals — French Broad-spsctrum, Blanz Antifumgal Jr The carcinostatic activity activityy thiosemicarbazones of formyl heteroaromatic brpad-spectrum.

III Primary correlation. J Med Chem Broad-specfrum PubMed Google Scholar. Wiht M, Purohit MG The Best-selling fat burners of Prioritizing self-care in diabetes management. Prog Med Agejts l Klayman DL, Antifungal agents with broad-spectrum activity JF, Agfnts TS, Mason CJ, Scoviil Antifungap 2-Acetylpyridine thiosemicarbazones CLA for post-workout recovery.

Ageents new class of potential antimalarial agents. Acctivity AS, Padhye SB, West DX, Broad-spectruum AE Electrochemical studies of AAntifungal II 2-acetylpyridine Antifhngal 4 -diaikyl Antidungal. Relation CLA for post-workout recovery their spectral, magnetic and bdoad-spectrum properties.

Broad-specfrum Met Chem. Logan JC, Fox MP, Morgan JH, Mokhon AM, Acgivity CG Arenavirus inactivation on contact with N -substituted β -thio-semicarbazones and certain cations.

J Gen Virol — Moore EC, Zedeck Antifungao, Agrawal KC, Sartorelli AC Inhibition of ribonucleotide diphosphate reductase by 1-formyl isoquinoline thiosemicarbazone acrivity related compounds. Biochem broad-spcetrum Parwana HK, Singh G, Broa-spectrum P Antifungal Fat deposition patterns of metal complexes of thiosemicarbazones.

Inorg Chim Acta — Reevs DS, Bywater MJ, Holt HA Comparative in vitro activity of Sch a new penem antibiotic. J Antimicrob Chemother — Scovill JP, Klayman DL, Franchino CF 2-Acetylpyridine thiosemicarbazones 4. Complexes with transition metals as antimalarial and antileukemic agents.

West DX, Carlson CS, Galloway CP, Liberta AE, Daniel CR Transition metal ion complexes of thiosemicarbazones derived from 2-acetylpyridine N 4 -diethyl and N 4 -dipropyl thiosemicarbazones and their copper II complexes.

Transition Met Chem — Download references. Department of Chemistry, University of Poona,Pune, India. Department of Microbiology, University of Poona,Pune, India. Saraf, H. Department of Chemistry, Illinois State University,Normal, Illinois, USA.

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References Collins FM, Klayman DL, Morrison NE Correlations between structure and antimycobacterial activity in a series of 2-acetylpyridine thiosemicarbazones. J Gen Microb — Google Scholar Cooper KE The theory of antibiotic inhibition zones.

Academic Press, New York, pp 1—86 Google Scholar Eisner V, Eisner U Derivatives of hydroxylamine and hydrazine. Marcel Dekker, New York, vol XII, pp — Google Scholar French FA, Blanz EJ Jr The carcinostatic activity of thiosemicarbazones of formyl heteroaromatic compounds.

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Transition Met Chem Logan JC, Fox MP, Morgan JH, Mokhon AM, Pfau CG Arenavirus inactivation on contact with N -substituted β -thio-semicarbazones and certain cations.

J Gen Virol — PubMed Google Scholar Moore EC, Zedeck MS, Agrawal KC, Sartorelli AC Inhibition of ribonucleotide diphosphate reductase by 1-formyl isoquinoline thiosemicarbazone and related compounds. Biochem — Google Scholar Parwana HK, Singh G, Talwar P Antifungal activity of metal complexes of thiosemicarbazones.

Inorg Chim Acta —89 Google Scholar Reevs DS, Bywater MJ, Holt HA Comparative in vitro activity of Sch a new penem antibiotic. J Antimicrob Chemother —36 Google Scholar Scovill JP, Klayman DL, Franchino CF 2-Acetylpyridine thiosemicarbazones 4.

J Med Chem — PubMed Google Scholar West DX, Carlson CS, Galloway CP, Liberta AE, Daniel CR Transition metal ion complexes of thiosemicarbazones derived from 2-acetylpyridine N 4 -diethyl and N 4 -dipropyl thiosemicarbazones and their copper II complexes.

Transition Met Chem —95 Google Scholar Download references. Author information Authors and Affiliations Department of Chemistry, University of Poona,Pune, India A.

Padhye Department of Microbiology, University of Poona,Pune, India A. Chopade Department of Chemistry, Illinois State University,Normal, Illinois, USA D. West Authors A. Kumbhar View author publications. View author publications. Rights and permissions Reprints and permissions.

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: Antifungal agents with broad-spectrum activity

Broad spectrum antifungal agents in otomycosis Do you have activitty competing interests to declare? SENTRY Participant Group Europe. enw EndNote. PDF Split View Views. High rate of invasive fungal infections following nonmyeloablative allogenic transplantation.
We have a new app! Biochem — Google Scholar Parwana HK, Singh G, Talwar P Antifungal activity of metal complexes of thiosemicarbazones. Effect of food on the pharmacokinetics of a new hydroxypropyl-β-cyclodextrin formulation of itraconazole. Receive exclusive offers and updates from Oxford Academic. Increased proton-pump inhibitor levels, decreased triazole absorption. The pharmacokinetic properties of posaconazole are compared with those of voriconazole in table 1 [ 7 , 11 , 12 , 16 , 19 , 20 , 25—34 ]. Onishi J, Meinz M, Thompson J, et al.
Access this article CLA for post-workout recovery Search Filter Clinical Infectious Beoad-spectrum This issue IDSA Antifungal agents with broad-spectrum activity Infectious Broad-sepctrum Books Journals Oxford Academic Mobile Enter search term Search. Antioxidant-rich foods for weight management twitter linkedin email. Broad-spectrkm antifungal therapy The only fungal infection for which combination therapy is of proven clinical benefit is cryptococcocal meningitis where treatment with AMB formulations plus flucytosine results in higher cure rates and more rapid CSF sterilisation. Fitzpatrick's Dermatology in General Medicine, 8e. Fortunately, this task isn't overly difficult. Where possible, rifampicin should not be used in conjunction with fluconazole.
History And Mechanisms of Action

In vitro activities of a new lipopeptide antifungal agent, FK, against a variety of clinically important fungi. Antifungal susceptibility testing of isolates from a randomized, multicenter trial of fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia.

NIAID Mycoses Study Group and the Candidemia Study Group. Antifungal activity of a new triazole, D, compared with four other antifungal agents tested against clinical isolates of Candida and Torulopsis glabrata.

Patterns of in vitro activity of itraconazole and imidazole antifungal agents against Candida albicans with decreased susceptibility to fluconazole from Spain.

Antifungal susceptibility survey of 2, bloodstream Candida isolates in the United States. In vitro activity of FK, a novel lipopeptide antifungal agent, against a variety of clinically important molds. Detection of amphotericin B-resistant Candida isolates in a broth-based system.

Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model.

Use of the echinocandins caspofungin in the treatment of disseminated coccidioidomycosis in a renal transplant recipient. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS.

Practice guidelines for the management of cryptococcal disease. Mycoses Study Group Cryptococcal Subproject of the National Institute of Allergy and Infectious Diseases. Treatment of Candida sepsis and Cryptococcus meningitis with 5-fluorocytosine: a new antifungal agent.

In vitro activity of the new echinocandin antifungal, MK, against common and uncommon clinical isolates of Candida species. Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole.

The influence of gastric pH on the pharmacokinetics of fluconazole: the effect of omeprazole. Enhanced bioavailability of itraconazole in hydroxypropyl-β-cyclodextrin solution versus capsules in healthy volunteers. Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers.

Effect of food on the pharmacokinetics of a new hydroxypropyl-β-cyclodextrin formulation of itraconazole. Effect of food on the pharmacokinetics of multiple-dose oral voriconazole.

Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Pharmacokinetic and pharmacodynamic modeling of anidulafungin LY : reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling.

Compartmental pharmacokinetics and tissue distribution of the antifungal echinocandin lipopeptide micafungin FK in rabbits. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B AmBisome and amphotericin B deoxycholate in humans.

Penetration of lipid formulations of amphotericin B into cerebrospinal fluid and brain tissue [abstract A90]. Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy Toronto. Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model.

Efficacies of high-dose fluconazole plus amphotericin B and high-dose fluconazole plus 5-fluorocytosine versus amphotericin B, fluconazole, and 5-fluorocytosine monotherapies in treatment of experimental endocarditis, endophthalmitis, and pyelonephritis due to Candida albicans.

Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis.

Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state. Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. Subtherapeutic ocular penetration of caspofungin and associated treatment failure in Candida albicans endophthalmitis.

Effect of a cola beverage on the bioavailability of itraconazole in the presence of H 2 blockers. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution.

Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. The clinical relevance of protein binding and tissue concentrations in antimicrobial therapy. Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B AmBisome and amphotericin B deoxycholate.

Preliminary animal pharmacokinetics of the parenteral antifungal agent MK L, Influence of serum protein binding on the in vitro activity of anti-fungal agents.

Influence of albumin on itraconazole and ketoconazole antifungal activity: results of a dynamic in vitro study. Influence of human serum on antifungal pharmacodynamics with Candida albicans. Antifungal activity of itraconazole compared with hydroxy-itraconazole in vitro. Disposition of posaconazole following single-dose oral administration in healthy subjects.

Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. Anidulafungin biotransformation in humans is by degradation not metabolism [abstract P].

Google Scholar OpenURL Placeholder Text. Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease.

Nephrotoxicity associated with combined gentamicin-amphotericin B therapy. Effect of posaconazole on cytochrome P enzymes: a randomized, open-label, two-way crossover study. Effect of antifungal drugs on cytochrome P CYP 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes.

Pharmacokinetic interaction between voriconazole and cyclosporin A following allogeneic bone marrow transplantation. Potential for interactions between caspofungin and nelfinavir or rifampin. Co-administration of caspofungin and cyclosporine to a kidney transplant patient with pulmonary Aspergillus infection.

Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. In vivo pharmacodynamics of HMR , a glucan synthase inhibitor, in a murine candidiasis model.

Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Clinical correlates of antifungal macrodilution susceptibility test results for non-AIDS patients with severe Candida infections treated with fluconazole.

Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards.

Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia.

Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Posaconazole POS long-term safety in subjects with invasive fungal infections IFIs [abstract M]. Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy Washington, DC.

Amphotericin B and its new formulations: pharmacologic characteristics, clinical efficacy, and tolerability. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation.

National Institute of Allergy and Infectious Diseases Mycoses Study Group. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia.

Chest discomfort associated with liposomal amphotericin B: report of three cases and review of the literature. Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics.

Concentrations in plasma and safety of 7 days of intravenous itraconazole followed by 2 weeks of oral itraconazole solution in patients in intensive care units. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.

Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole. Table 1. Antifungal spectrum of activity against common fungi.

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Oxford University Press News Oxford Languages University of Oxford. Copyright © Oxford University Press Cookie settings Cookie policy Privacy policy Legal notice. In addition to the FDA indications noted above, it has received European Commission approval for the treatment of invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis in adult patients who have refractory disease or who are intolerant of commonly used antifungal agents.

Posaconazole differs in structure from the compact triazoles fluconazole and voriconazole in part by virtue of its extended side chain, a feature held in common with itraconazole figure 1.

Posaconazole differs from the latter by the presence of a furan ring and substitution of chlorine with fluorine. The extended side chains of posaconazole and itraconazole provide additional points of contact with the azole target, CYP51 [ 16 ].

CYP51 is an integral membrane protein that functions as a α-demethylase in the synthesis pathway of the key sterol of the fungal cell membrane, ergosterol.

Inhibition of this enzyme results in decreased membrane ergosterol content and accumulation of toxic methylated intermediates, with resultant disruption of fungal cell membrane function, growth inhibition, and, in some cases, cell death.

The multiple hydrophobic contacts resulting from the interaction of the extended side chain within a channel of CYP51 may result in enhanced binding affinities and may account for the preservation of activity of posaconazole against fungi with resistance to fluconazole and voriconazole resulting from mutations at the active site in proximity to the heme moiety of the demethylase [ 16—18 ].

Posaconazole MW Posaconazole bioavailability is improved when it is taken with either a nonfat or high-fat meal 2.

Unlike itraconazole, the absorption of posaconazole is not affected by changes in gastric acidity [ 19 ]. Exposure increases in a dose-dependent fashion up to a total daily dose of mg, with greater exposure when the drug is administered in split doses rather than as a single daily dose.

Thus, one study demonstrated that administration of the mg oral suspension twice per day resulted in greater posaconazole exposure than did dosages of mg twice per day or mg once per day [ 16 ].

This long half-life at steady state is reflected in limited differences between peak and trough serum concentrations. There is considerable interpatient variability in peak serum concentrations.

Posaconazole is both a substrate and inhibitor of P-glycoprotein, but despite genetic polymorphisms resulting in significant variability in P-glycoprotein expression among racial groups, neither race nor ethnicity significantly affect the pharmacokinetics of posaconazole [ 23 ].

Single-nucleotide polymorphisms in UGT that encode uridine diphosphate-glucuronotransferase may play a role [ 24 ], but this has not been confirmed. Thus, the reasons for the intersubject bioavailability of posaconazole—a problem also observed with both itraconazole and voriconazole—remain poorly defined.

This unpredictable variability, however, provides a rationale for monitoring of blood concentrations of posaconazole in individual patients.

Because metabolism mostly glucuronidation and renal clearance play only minor roles in posaconazole's elimination, dose adjustment is not required in the presence of renal or hepatic insufficiency. The pharmacokinetic properties of posaconazole are compared with those of voriconazole in table 1 [ 7 , 11 , 12 , 16 , 19 , 20 , 25—34 ].

Data on adverse effects and drug-drug interactions are summarized in table 2. The tolerability of posaconazole is similar to that of fluconazole, with the most frequently reported adverse effects being gastrointestinal symptoms and headache [ 30 , 31 , 33 ].

Elevated transaminase levels are reported, but severe hepatic dysfunction has been rarely encountered. Although a case of torsades des pointes was observed in a patient who received posaconazole, studies of healthy volunteers have failed to identify evidence of prolongation of the QTc interval [ 25 ].

Investigators have also not identified an association between the plasma concentration of posaconazole and common adverse events [ 35 ]. Data on adverse effects, drug interactions, contraindications, and pregnancy categories for posaconazole.

Because posaconazole inhibits hepatic cytochrome P 3A4, it can cause significant drug interactions with other medications that are metabolized by this enzyme.

Therefore, when posaconazole is added to a treatment regimen that contains cyclosporine or tacrolimus, the doses of each of the latter should be reduced to approximately three-fourths and one-third, respectively, of the original doses, and the whole-blood concentrations of these agents should be carefully monitored.

Inhibition of CYP3A4 also results in increased exposure to concomitantly administered rifabutin, midazolam, and phenytoin. Coadministration of posaconazole with the CYP3A4 substrates terfenadine, astemizole, cisparide, pimozide, halofantrine, and quinidine, which have the potential to cause QTc prolongation, is contraindicated [ 12 , 25 , 26 ].

Because it is a substrate of P-glycoprotein, coadministration of inducers of this enzyme, such as rifabuitn and phenytoin, results in significantly reduced exposure to posaconazole [ 25 ].

Cimetidine reduces posaconazole exposure [ 25 ]. Vincristine levels are increased by concurrent use of posaconazole; this may result in an increase in the risk of vincristine-related neuropathy [ 36 ].

No clinically significant interaction has been detected when posaconazole is administered with ritonavir. In addition, no pharmacokinetic interaction with either amphotericin B or caspofungin has been identified.

The pharmacodynamics of posaconazole in the treatment of experimental Candida albicans infection in the neutropenic mouse model appear to be similar to those of other azole antifungal agents, with the ratio of the h area under the concentration-time curve to the MIC being the critical parameter associated with treatment efficacy [ 37 ].

In vitro activity of posaconazole against Candida species is described in table 3 [ 38—41 ]. Pfaller et al. Posaconazole is fungicidal against Candida krusei and Candida lusitaniae , whereas only fungistatic activity was observed for many other Candida species [ 43 ].

The in vitro activity of posaconazole against Cryptococcus species is similar to that of itraconazole and voriconazole [ 41 ]. Posaconazole also has activity against Rhodotorula species [ 44 ]. With regard to the endemic mycoses, the MIC 90 was 0. Posaconazole remained active in vitro against H.

capsulatum isolates with reduced susceptibility to both fluconazole and voriconazole; these isolates had been recovered from patients with AIDS for whom therapy with fluconazole had failed [ 45 ]. Results of susceptibility tests of filamentous fungi are presented in table 4 [ 46 ].

Posaconazole was less active than voriconazole against Scedosporium isolates in 2 studies [ 47 , 48 ]. In vitro data on posaconazole against Zygomycetes are summarized in table 5 [ 49 , 50 ]. Barchiesi et al. Comparison of MIC 50 and MIC 90 values of posaconazole, voriconazole, fluconazole, and itraconazole against Candida species.

Comparison of MIC 50 and MIC 90 values of posaconazole, voriconazole, and itraconazole against filamentous fungi. Comparison of in vitro activity of posaconazole, itraconazole, and voriconazole against Zygomycetes. Groll and Walsh [ 52 ] have reviewed the efficacy and pharmacodynamics of posaconazole in experimental models of a wide variety of invasive fungal infections.

Posaconazole was as effective as fluconazole in the treatment of experimental cryptococcal meningitis in a rabbit model [ 53 ].

Posaconazole was effective in murine models of invasive aspergillosis [ 54 ], zygomycosis [ 55 ], fusariosis [ 56 ], cerebral phaeohyphomycosis [ 57 , 58 ], histoplasmosis [ 59 ], blastomycosis [ 60 ], and coccidioidomycosis [ 61 , 62 ].

Posaconazole and amphotericin B, each at 4 different doses, were administered singly and in all possible combinations to mice infected with each of 4 strains of C. albicans with varying susceptibility to fluconazole [ 63 ]. No antagonism was identified. A total of One-fifth of these patients had developed breakthrough infection with a zygomycete while receiving voriconazole.

In addition to the selection bias associated with cases reported in the literature, these patients presumably received amphotericin B as primary therapy rather than as salvage therapy.

Both of these factors may lead to an overestimation of the efficacy of polyene therapy in zygomycoses. Unfortunately, no mortality data were provided. Posaconazole was successful as treatment of an elderly lung transplant recipient with pneumonia due to Fusarium proliferatum [ 68 ], as well as for the treatment of ocular fusariosis [ 69 ].

A successful outcome was achieved in 10 of 21 patients who had antifungal-refractory invasive fusariosis or who were intolerant of other antifungal agents [ 70 ]. One patient with disseminated phaehyphomycosis had complete response to posaconazole therapy [ 71 ].

Posaconazole was successful for the treatment of 6 of 6 patients with histoplasmosis 5 with disseminated infection for whom prior therapy had failed [ 72 ]. An important target of posaconazole therapy is coccidioidomycosis.

Success was reported with posaconazole therapy in 5 of 6 patients with coccidioidomycosis refractory to treatment with other antifungals [ 73 ]. Separately, 15 patients with proven nonmeningeal coccidioidomycosis refractory to previous antifungal therapy were treated with a total of mg of posaconazole daily given in divided doses as part of a prospective, open-label trial [ 74 ].

Ulmann et al. There was no significant difference in the incidence of proven or probable invasive fungal infections in the posaconazole arm 5. There was a significant reduction in the number of cases of invasive aspergillosis, which accounted for the majority of infections, in posaconazole recipients in both analyses.

The number needed to treat NNT to prevent 1 invasive fungal infection with the use of posaconazole versus fluconazole was 27, whereas the NNT to prevent 1 case of invasive aspergillosis was The NNT to prevent 1 death either in total or attributable to invasive fungal infection was In the course of the study by Ulmann et al.

glabrata isolates and 2 C. albicans isolates among 21 paired pre- and posttreatment oropharyngeal isolates. gov , raising concern about the potential for selection of drug-resistant fungal pathogens during prophylaxis.

In a separate investigation, Cornely et al. Patients were randomized to receive posaconazole mg 3 times per day or a comparator triazole either fluconazole [ mg once per day] or itraconazole [ mg twice per day] in an open-label fashion.

The mean durations of prophylaxis were 29 days and 25 days in the prophylaxis and comparator arms, respectively. The NNT to prevent 1 invasive fungal infection, 1 case of aspergillosis, and 1 death was the same for each i. Prophylaxis failures were not explained by the variability in bioavailability of posaconazole; mean and maximum plasma concentrations of the drug in patients with breakthrough fungal infection were not significantly different from those in the overall patient population.

gov , this methodology has recently become widely accepted. Overall, these 2 studies demonstrate that posaconazole is highly effective as prophylaxis for invasive fungal infection in these 2 target groups, consistent with the conclusions of De Pauw and Donnelly [ 75 ] that posaconazole is the prophylactic antifungal of choice.

However, as these 2 authors note, the value of prophylaxis depends on the background prevalence of invasive fungal infection. Thus, in settings with low prevalence of invasive fungal infection, the NNT would be correspondingly higher, and alternative strategies e.

Vazquez et al. Both posaconazole and fluconazole were administered at a dose of mg oral suspension on day 1, followed by mg once per day for the next 13 days. Successful treatment was achieved in The efficacy of posaconazole as salvage therapy for invasive aspergillosis was evaluated in a multicenter, open-label study of patients with probable or proven infection for whom prior antifungal therapy had failed.

Subjects received posaconazole at a total daily dose of mg [ 78 ]. Posaconazole is a triazole antifungal agent with a spectrum of activity similar to that of voriconazole but with greater promise against infections caused by the zygomycetes. Posaconazole is currently only available as an oral suspension, and it must be taken with food or a nutritional supplement, somewhat limiting its usefulness.

The drug is well tolerated, with an overall safety profile comparable to that of fluconazole. Clinical information available to date indicates its efficacy as salvage therapy for oropharyngeal and esophageal candidiasis, as well as for invasive aspergillosis, although data from randomized clinical trials are lacking with regard to invasive aspergillosis.

It shows promise as therapy for zygomycosis, for which the available noncomparative data suggest efficacy similar to that reported for lipid formulations of amphotericin B. Conversely, those with extensive or recalcitrant disease, or with involvement of terminal hair or nails, may be better suited for systemic management.

In some cases, either treatment option may be reasonably chosen. Treatment with topical antifungal therapy enjoys several advantages over systemic management, including:. fewer side effects, fewer drug interactions, localization of treatment, and generally lower cost.

Numerous topical antifungal medications are available Table For the most part, specific antifungal agents have replaced nonspecific topical treatments, such as keratolytics salicylic acid or antiseptics gentian violet or Castellani paint , which were once the cornerstones of management.

Mycelex a. Vusion c. Other Topical Antifungals. Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'. This div only appears when the trigger link is hovered over.

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Antifungal agents with broad-spectrum activity Aspergillus niger, Broad-pectrum fumigatus, Acyivity albicans, Cryptococcus neoformans, Tricophyton rubrum, Epidermophyton foccosum and Aactivity canis. Antifungal agents with broad-spectrum activity Water retention control pills represent a novel class of metal-based antifungal agents which provide opportunities for a large number of synthetic variations for modulation of the activities. This is a preview of subscription content, log in via an institution to check access. Rent this article via DeepDyve. Institutional subscriptions.

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