For antifungal therapy Amphotericin B (also called liposomal preparation), various azole derivatives, echinocandins and flucytosine (see Table: Some drugs for systemic fungal infections). Amphotericin B, an effective but relatively toxic drug that is the cornerstone of antifungal therapy for invasive fungal infections and severe long. However, recent potent and less toxic triazoles and echinocandins are now often recommended as a first-line drugs for many invasive fungal infections. These drugs have significantly changed the approach of antifungal therapy and sometimes even allow oral treatment of chronic fungal infections. Some drugs for systemic fungal infections drug applications dose Some side effects Amphotericin B Most fungal infections (Not for Pseudallescheria sp) Conventional (deoxycholate) administration: 0.5-1.0 mg / kg i.v. 1 times a day Conventional administration: Acute infusion reactions, neuropathy, gastrointestinal complaints renal failure, anemia, bone marrow injuries, thrombophlebitis, hearing loss, skin rash, hypokalemia, hypomagnesemia Various liposomal forms: 3-5 mg / kg IV 1 times daily Liposomal forms: infusion reactions *, renal failure * anidulafungin candidiasis including candidemia 200 mg iv on day 1, then 100 mg i.v. In esophageal candidiasis, half this dose hepatitis, diarrhea, hypokalemia, infusion reactions caspofungin aspergillosis candidiasis including candidemia 70 mg iv 1 times a day on day 1, then 50 mg i.v. po 1 times daily phlebitis, headache, gastrointestinal symptoms, rash fluconazole mucosa and systemic candidiasis cryptococcal Kokzidioidomeningitis 100-800 mg or iv 1 times daily (initial dose can be given) children: 3-12 mg / kg p.o. or iv 1 times a day gastrointestinal symptoms, hepatitis, QT prolongation flucytosine candidiasis (systemic) cryptococcosis 12.5 to 37.5 mg / kg p.o. Pancytopenia po 4 times a day because of bone marrow toxicity, neuropathy, nausea, vomiting, liver and kidney damage, colitis isavuconazole aspergillosis mucormycosis 372 mg or iv every 8 h (6 doses) initially, then 372 mg p.o. or iv once / day for maintenance nausea, vomiting, hepatitis itraconazole Dermatomycoses histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis 100 mg po to 200 mg po 1 times a day 2 times daily hepatitis, gastrointestinal problems, skin rash, headache, dizziness, hypokalemia, hypertension, edema, QT prolongation micafungin candidiasis including candidemia 100 mg iv 1 times daily (150 mg dose in esophageal candidiasis) phlebitis, hepatitis, rash, headache, nausea posaconazole prophylaxis for invasive aspergillosis and candidiasis 200 mg po tid hepatitis, gastrointestinal problems, skin rash, QT prolongation Oropharyngeal candidiasis 100 mg po 2 times a day on day 1, then 100 mg of 1 times a day for 13 days against itraconazole-resistant oropharyngeal candidiasis 400 mg po 2 times daily voriconazole Invasive aspergillosis Fusariosis Scedosporiosis 6 mg / kg i.v. p.o. for 2 initial doses, then 200 mg every 12 h or 3-6 mg / kg i.v. every 12 h gastrointestinal discomfort, temporary visual impairment, peripheral edema, skin rash, hepatitis, QT prolongation * This side effect is less frequent than with the conventional administration with lipid administrations. Isavuconazole is given for the prodrug Isavuconazonium; 372 mg isavuconazonium are equivalent to 200 mg isavuconazole. Clinical calculator: QT interval correction (ECG) Amphotericin B Amphotericin B is the cornerstone of antifungal therapy for invasive and deep mycosis, but other antifungals (. Eg fluconazole, voriconazole, posaconazole, the echinocandins) are now as First- drawn line drugs for many of these infections into consideration. Although amphotericin B does not have good CSF penetration, it is still effective against certain fungal infections such as cryptococcal meningitis. In chronic mycosis usually with amphotericin B-deoxycholate is ? 0.3 mg / kg i.v. started one times a day and to the desired target dose with good tolerance (0.4-1.0 mg / kg, not generally> 50 mg / day) increased; many patients tolerate the desired target dose as early as 1 day. In acute, life-threatening fungal infections amphotericin B deoxycholate can with 0.6-1.0 mg / kg / i.v. begin 1 times daily. There are two administrations administrations of Amphotericin: deoxycholate (standard) lipid based The standard application, amphotericin B deoxycholate, in 5% glucose solution must be given ever since salts to form a precipitate of the substance may cause. The infusion is administered mostly over 2-3 hour period, in selected patients but also more rapid infusions may be given over 20-60 minutes. However, more rapid infusions have no advantage in general. Many patients experience chills, fever, nausea, vomiting, loss of appetite, headache, and occasionally hypotension during and for several hours after an infusion. Amphotericin B may also cause a chemical thrombophlebitis, when administered via the peripheral venous; a central venous catheter may be preferred. Often a Vorbehnadlung with acetaminophen or NSAIDs is applied; if they are invalid, hydrocortisone is sometimes administered 25-50 mg or 25 mg diphenhydramine in addition. Often the hydrocortisone can be tapered during a prolonged therapy and omitted. Severe chills and rigors can meperidine 50-75 mg iv be mitigated or avoided. Various lLipidträger reduce the toxicity of amphotericin B (particularly nephrotoxicity and infusion-related symptoms). Two products are available: amphotericin B lipid complex Liposomal Amphotericin B Lipid formulations are compared to conventional amphotericin B are preferred because they Its main side effects are less infusion-related symptoms and less nephrotoxicity verursachen.Nebenwirkungen nephrotoxicity hypokalemia hypomagnesemia myelosuppression The greatest toxic risk of amphotericin B treatment consists of an impairment of kidney function. Serum creatinine and serum urea should be monitored before treatment and periodically during treatment: several times / week for the first 2-3 weeks, then once / month as clinically indicated 1-4. Amphotericin B is so far an exception among the nephrotoxic anti-infectives, as it is not excreted to a significant degree via the kidneys and is not cumulative with an increasing kidney failure. Nevertheless, the dose should be reduced or alternatively, a lipid formulation can be used if serum creatinine to> 2.0-2.5 mg / dl (> 177-221 micromol / L) or the blood urea nitrogen (to> 50 mg / dl> 18 mmol / l) increases. Acute nephrotoxicity may by aggressive i.v. Hydration will be reduced with brine before amphotericin B infusion of at least 1 liter of physiological saline should be given before the Amphotericininfusion. Mild to moderate amphotericin B-induced renal dysfunction usually disappear after cessation of therapy again slowly. Permanent damage are primarily before after prolonged therapy; for a total dose of> 4 g approximately 75% of patients have permanent kidney failure. Amphotericin B also suppresses often the bone marrow function, as manifested primarily as anemia. Hepatotoxicity or other adverse effects are uncommon. Azole antifungals azoles block the synthesis of ergosterol, an important component of the cell membrane of fungi. They can be administered orally, to treat chronic fungal infections. The first of these substances oral, ketoconazole, was more effective, less toxic triazole derivatives such. As fluconazole, itraconazole, posaconazole and Voricanozol replaced. Interactions may occur with all azoles, but are less likely to fluconazole. The listed below drug interactions are not intended as a complete list; Clinicians should consider establishing a specific reference to drug interactions for advice before using azole antifungals. Tips and risks interactions with medicines and food often occur with azole antifungals; all substances simultaneously used should be checked prior to prescribing. Fluconazole This water-soluble drug is almost completely absorbed after oral administration. It is almost excreted unchanged in the urine and has a serum half-life of> 24 hours, which once daily administration allowed. It penetrates well into the cerebrospinal fluid (? 70% of serum levels) and is particularly useful in the treatment of Kryptokokken- and Kokzidioidomeningitis. It is also one of the first-line drugs for the treatment of candidemia in non-neutropenic patients. Doses of 200-400 mg p.o. up to 800 mg 1 time 1 time daily daily in some severely ill patients and in patients (not C. albicans or C. krusei) infected with Candida glabrata or Candida sp other; Daily doses ? 1000 mg can be given and have an acceptable toxicity. Adverse effects that may occur most frequently, are gastrointestinal symptoms and rash. More severe toxicity is unusual, but the following have occurred: hepatic necrosis, Stevens-Johnson syndrome, anaphylaxis, alopecia, and if taken for a long period during the first trimester of pregnancy, fetal congenital anomalies. Drug interactions occur with fluconazole less frequently than with other azoles. However, fluconazole occasionally leads to increased serum levels of calcium channel blockers, cyclosporine, rifabutin, phenytoin, tacrolimus, oral anticoagulants Warfarintyp, sulfonylureas such. Tolbutamide or zidovudine. Rifampicin can reduce blood levels of fluconazole erniedrigen.Itraconazol This medicine has been the standard treatment for lymphokutaner sporotrichosis as well as mild to moderate curves of histoplasmosis, blastomycosis and paracoccidioidomycosis. It is also effective in mild cases of invasive aspergillosis, some cases of coccidioidomycosis and certain forms of Chromoblastomycosis. Despite its poor Liquorpenetration, itraconazole can be applied for the treatment of some forms of fungal meningitis, although it is not the drug of choice here. Due to its high lipid solubility and protein binding, however, the itraconazole blood levels are relatively low tissue levels itypischerweise high. The drug levels in urine and cerebrospinal fluid are negligible. The use of itraconazole has declined, while the use of voriconazole and posaconazole has risen. At doses up to 400 mg / day, it is mainly to gastrointestinal side effects, some men have reported also about erectile dysfunction. Higher doses can cause hypokalemia, hypertension and edema. It was also reported allergic rashes, hepatitis and hallucinations. A black Warnungsbox the FDA for heart failure has been issued, mainly for a total daily dose of 400 mg. Interactions with drugs and food can be significant. When the capsule form is used to improve acidic drinks (eg. As cola, sour fruit juices) or food (especially high fat foods), the absorption of itraconazole of the GI tract. but absorption may be lowered when itraconazole is given together with prescription or non-prescription stomach acid blockers. Various drugs, including rifampin, rifabutin, didanosine, phenytoin and carbamazepine, may reduce the serum levels of itraconazole. Itraconazole also inhibits the metabolic degradation of other drugs, which increases the blood levels and has potentially serious consequences. Concomitant administration of cisapride (not available in the US and in Germany) or some antihistamines (eg. As terfenadine, astemizole, loratadine possibly) can cause serious, even fatal cardiac arrhythmias. Rhabdomyolysis has been associated with itraconazole-induced increases in blood levels of cyclosporin or by statins. Serum levels of some drugs (eg. Digoxin, tacrolimus, oral anticoagulants, sulfonylureas) may increase when these drugs werden.Posaconazole administered with itraconazole The triazole posaconazole is available as an oral suspension and ale tablet. I.v. Formulation is likely to be available soon. This drug is very effective against yeasts and molds and treated various opportunistic mold infections effectively, such as those caused by Dematiaceous- (dark-walled) fungi (for. Example, Cladophialophora sp). It is the only oral azole causing against many species of mucormycosis is effective. Posaconazole may also be used for fungal prophylaxis in neutropenic patients with various tumors and in recipients of bone marrow transplants. Among the side effects of posaconazole as other triazoles include a prolonged QT interval and hepatitis. Occur on interactions with many drugs, including rifabutin, rifampin, statins, various immunosuppressants and Barbiturate.Voriconazol This broad-spectrum triazole i.v. as a tablet and a Formulation available. It is considered the drug of choice for the treatment of Aspergillus infections in immunocompetent and immunocompromised patients. Voriconazole may apiospermum also for the treatment of infections caused by Scedosporium and Fusarium are applied. Furthermore, the substance Candida esophagitis and invasive candidiasis is effective, although it is not considered a first-line treatment in general; it is effective against a wider range of Candida sp as fluconazole. Among the side effects that need to be observed for hepatotoxic disorders include hepatotoxicity, visual disturbances (common), Hallizunationen and dermatological reactions. This drug can prolong the QT interval. There are numerous drug interactions, especially with certain, used after organ transplants immunosuppressants. Echinocandins echinocandins are water-soluble lipopeptides that inhibit glucan synthesis. They are just only for i.v. Administration available. Their mechanism of action is unique among antifungal agents; Echinocandins target the cell wall, making them attractive because there is no cross-resistance with other drugs, their effects are fungicidal and there is no “mammalian counterpart” The drug levels in urine and cerebrospinal fluid are not significant. The echinocandins available in the US are anidulafungin, caspofungin and micafungin. There is little evidence to suggest which one is better of these drugs, but anidulafungin appears to interact with less medication than the other two. These drugs are potent fungicides against most clinically relevant Candida sp, but are considered fungistatic against Aspergillus. Side effects include hepatitis and rash. Flucytosine flucytosine, a nucleic acid analog, is water soluble and is well absorbed after oral administration. Often resistance already exists or develops, so it is almost always with other antifungal agents (usually amphotericin B) is applied together. Flucytosine plus. Amphotericin B is used primarily for treatment of cryptococcosis, but is also effective in some cases of disseminated candidiasis (including endocarditis), another scion of fungal infections and severe invasive aspergillosis. Flucytosiin plus. Antifungal azoles may have a benefit in cryptococcal meningitis and certain other fungal infections. The usual dose of 12.5 to 37.5 mg / kg p.o. 4 times a day resulting in high levels in serum, urine and cerebrospinal fluid. The main side effects are bone marrow suppression (thrombocytopenia and leukopenia), hepatotoxicity and enterocolitis; only the extent of bone marrow suppression is proportional to the serum levels. Because flucytosine is mainly excreted renally, it comes to an increase in serum levels when set during the concomitant use of amphotericin B nephrotoxic effects, particularly when amphotericin B is used in doses of> 0.4 mg / kg / day. Flucytosinserumspiegel should be monitored and the dose adjusted accordingly in order to keep the mirror between 40 and 90 ug / ml. 2 times per week, a full blood analysis and monitoring of renal and liver function tests should be made. When a serum level determination is not available, treatment with 25 mg / kg four times a day started and the dose if there are indications lowered to renal dysfunction.