antifungal agents, fungal infection, mycoses, nose and paranasl sinuses
P Parida. Medical management of invasive fungal sinusitis. The Internet Journal of Otorhinolaryngology. 2006 Volume 7 Number 1.
The incidence of fungal infection continues to rise as the population of immunocompromised individuals increases. Despite the enlarging numbers of infections, there are only a few antifungal agents for treatment of deep seated invasive infections. This article focuses on general concepts of antifungal therapies and provides a detailed review of each antifungal agent available for treatment of deep seated mycoses of nose and paranasal sinuses.
Treatment of fungal sinusitis depends on accurate diagnosis of the type of fungal sinusitis. There are two basic types of fungal sinusitis: invasive and noninvasive. Invasive fungal sinusitis are of two types; acute invasive and .chronic invasive (both granulomatous and non-granulomatous).The non-invasive fungal sinusitis are of 3 types (1).fungal balls (mycetoma), (2).saprophytic colonization, and (3).allergic fungal sinusitis (AFRS).This classification is founded on the immunologic relation of the fungus to the host 1 .
Fulminant (acute) invasive fungal sinusitis: Regulation of diabetes mellitus and a decrease in the dose of immunosuppressive drugs facilitate the treatment. Reversibility of the immunocompromised state is mandatory to control the spread of infection. The mainstays of treatment are extensive debridement of craniofacial lesion till the tissue bleeds and antifungal drugs, of which amphotericin B is most commonly used. Granulocyte colony stimulating factor and hyperbaric oxygen are occasionally used.
Chronic indolent fungal sinusitis: Surgical debridement and a prolonged course of antifungal agent are required to treat this condition.
Principles of antifungal treatment
Correct identification of the fungus
Use of standard published antifungal regimens
Clinician should consider initial therapy as an induction phase with optimization in both dose and antifungal drug, which gives maximum fungicidal activity at site of infection; consider combination therapy in certain cases.
Control of underlying medical or immunosuppressive conditions is mandatory.
Clinician must pay particular attention to the drug interaction, pharmacokinetics, and resulting toxicities; this may require measurement of drug levels in certain circumstances.
After apparent stabilization of clinical symptoms and signs of infection with treatment, consideration of a consolidation drug regimen in dose or drug to complete a defined course of therapy is required.
Follow-up for relapse/reinfection after treatment should be at least 6 months to a year depending on fungus and type of infection.
Amphotericin B is a polyene antifungal agent, with antifungal activity first isolated by Gold et al from
Mechanism(s) of Action
Amphotericin B binds to sterols, preferentially to the primary fungal cell membrane sterol, ergosterol. This binding disrupts osmotic integrity of the fungal membrane, resulting in leakage of intracellular potassium, magnesium, sugars, and metabolites and then cellular death 3,4 .
Immediate Adverse Effects and Premedication
Acute reactions to amphotericin B are seen within 90 minutes of the infusion and usually remit by 3-4 hours. Most common is fever with or without chill and rigors, headache, nausea, vomiting, malaise and generalized aches. Hypotension and anaphylaxis are rare. Up to 50% of patients will have immediate infusion-related adverse reactions 11 . Tolerance to the immediate reactions usually develops over time. Therefore if premedications are used in the treatment course, their need should be reevaluated weekly.
Acetaminophen 650-1000 mg per oral /per rectal. 30 minutes prior to amphotericin B. Other non-steroidal anti-inflammatory drugs (NSAIDS) like aspirin, ibuprofen and diphenylhydramine can be used if not contraindicated 4,5,6 . Hydrocortisone: if patients experience severe rigors with previous infusion, start at 25 mg IV 30 minutes prior to amphotericin B (may increase to 50 mg and can be added directly to the transfusion bottle 5 ).Nausea and vomiting generally are managed by administration of phenothiazines such as prochlorperazine or promethazine. Meperidone is used most commonly for the treatment of amphotericin-B related rigors 7 .
It occurs up to 80% of patients, manifested by azotemia, eletrolyte wasting (potassium and magnesium), a decrease in urinary concentrating ability, distal renal tubular acidosis 4,5,8 . It is usually reversible after cessation of the drug. Sodium loading may minimize azotemia (administer 500 ml of normal saline both before and after amphotericin B infusion 8,9 ).Other nephrotoxic drugs should be avoided if possible. If azotemia occurs with a serum creatinine> 3 mg/dl, the dose of amphotericin B may be reduced or held after a careful assessment of the risks versus benefits to the patient.
Phlebitis can occur with infusion via peripheral veins 4,10 . If peripherally administered, concentration should not exceed 0.1 µg/ml of D5W. Phlebitis can be prevented by decreasing the rate of infusion or further diluting infusion, adding heparin 1000 units/L to the solution, using central vein and rotating the infusion site 4 .
Other less common adverse effects
Normochromic, normocytic anemia with decrease in hemoglobin of up to 35% from baseline has been reported routinely following extended therapy with amphotericin B 4,5,10 . The proposed mechanism is a direct suppression of erythropoietin production and a decrease in the production of erythrocytes that may occur in patients with deteriorating renal function 11,12 . Neutropenia and thrombocytopenia is associated infrequently with amphotericin B therapy 4,10,13 .
Usual dose is 0.25-1.0mg/kg/day (most commonly 0.4 to 0.7 mg/kg/d 4,10 ). Maximum daily dose-1.2mg/kg/day in adults and 1.5mg/kg/day in children. Alternate day therapy - double the daily dose to a maximum of 1.5 mg/kg/d. Liposomal amphotericin-B-1-5 mg/kg, ABLC-5mg/kg/day, ABCD-3-5mg/kg/day.Total cumulative dose is of 2-4gms (4-6 gms in case of intracranial extension).
Prior to starting treatment, a test dose of 1 mg of amphotericin B in 50 ml of 5% is usually infused over 20 minutes in order to assess the patient for immediate adverse events 4,10 . The patient's vital signs are monitored every 15 minutes for an hour. If no serious adverse reactions occur, the remainder of the desired daily dose is administered over 2-6 hours as follows: Doses
Monitoring in Patients Receiving Amphotericin B:
The following should be monitored more aggressively during the therapy:
1. Blood urea nitrogen, Serum-creatinine-twice a week, 2. Potassium, magnesium, sodium, and other electrolytes-twice a week, and 3. Complete blood count-once a week.
Amphotericin B still remains as the mainstay of antifungal therapy. Its lipid formulations, on the other hand, are promising due to their ability to reduce the toxicity of amphotericin B. They are currently licensed for use when amphotericin B therapy fails or is unacceptably toxic. The use of lipid formulations in specific clinical settings is under continuing investigation.
Liposomal Amphotericin B (L-AMB)
Liposomal amphotericin B (L-AMB) is a lipid formulation of amphotericin B 10,14,15,16 . the major goal of developing L-AMB has been to attain a compound with lower toxicity and with at least similar efficacy compared to the parent compound, amphotericin B deoxycholate. L-AMB is composed of amphotericin B complexed with hydrogenated phosphatidylcholine, distearoyl-phosphatidylglycerol, and cholesterol. Unlike the other lipid formulations of amphotericin B, it is a true liposome composed of unilamellar lipid vesicles. Compared to the other lipid formulations of amphotericin B, L-AMB reaches higher concentrations in plasma and remains in the circulation longer. Similar to the other lipid formulations, L-AMB concentrates in reticuloendothelial system 10,14,15,16 . This finally provides a persistent pool of L-AMB in plasma and a sustained delivery to the site of infection. L-AMB attains high concentrations in brain tissue. Elimination of L-AMB from serum is biphasic. This pattern suggests that L-AMB is first concentrated in reticuloendothelial system cells and then is redistributed.
L-AMB is used as a salvage agent when amphotericin B therapy fails or is unacceptably toxic 14,15 . It is not a first-line drug for any of the fungal infections. It is also licensed as an empirical therapeutic agent in febrile neutropenia not responding to broad spectrum antibiotic treatment more than 96 hours. Its potency in different clinical settings is under continuing investigation. Among the lipid amphotericin B formulations, L-AMB is one of the more commonly used preparations
1. L- amphotericin B
Azole Antifungal Drugs
They are Imidazoles and triazoles.Imidazoles are clotrimazole, miconazole, and ketoconazole.Two important triazoles are itraconazole and fluconazole.
Mechanism of action
In general, the azole antifungal agents are thought to work principally by inhibiting the cytochrome P450 14a-demethylase (P45014DM) 10,17,18 . This enzyme is involved in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Inhibition of this enzyme leads to accumulation of lanosterol that in turn leads to perturbation of the fungal cell membrane.
Side effect of the azoles
Gastrointestinal upset-Most common. Mild elevation in liver enzymes occurs in 1-7% of patients. Rash and headache are less common. Alopecia-following long course of therapy with high dose fluconazole. Aldosterone like effect with hypertension, hypokalemia and peripheral extremity edema when dose of itraconazole exceeds >600mg/day.All azoles have the potential for embryotoxicity and teratogenicity. Azoles should not be given during pregnancy.
Dosages and preparations-the triazole
INTRAVENOUS ITRACONAZOLE: The excipient for the intravenous formulation of both itraconazole and voriconazole is cyclodextrin 20 . As cyclodextrin is renally excreted, the intravenous formulation of these drugs should be carefully used in patients who have renal impairment particularly when a ceatinine clearance is < 50 ml/min 21 .
Dosing-200 mg ,IV, BD for 4 Doses followed by oral 200mg,IV, OD for 2Wks
Echinocandins: (Caspofungin, Micafungin, Anidulafungin)
Echinocandins belong to a new class of antifungal agents that inhibits enzyme 1, 3-B-D-glucan synthase in the fungal cell wall, and it appears to have fewer side effects in humans 10,23,25,26 . Approved by the FDA for the treatment of invasive aspergillosis that is refractory to conventional therapies. ROUTE OF ADMINISTRATION AND DOSE:
Combination and Sequential Therapy
Having more than one site of antifungal action, combination therapy potentially reduces the likelihood for emergence of resistant strains. Improvement has been noted with amphotericin B or itraconazole followed by voriconazole but not with itraconazole followed by amphotericin B. Because in vitro animal data suggest antagonism, simultaneous therapy with amphotericin B and an azole should be employed with caution. However, it appears that sequential therapy with an azole to complete a course of therapy after treatment with amphotericin B is probably safe. Theoretically, there appears to be a sequence-specific antagonism when amphotericin B is used in patients previously treated with an azole, and these patients could be at risk for treatment failure. This is presumably because the azoles inhibit ergosterol formation that eliminates the site of action of amphotericin B. However, there are no clinical data that have implicated previous azole therapy as a cause of treatment failure in
For Aspergillosis Amphotericin-B+Flucytocin shows synergistic action 10 , Amphotericin-B+Imidazole- demonstrated both synergism and antagonism 29 , Amphotericin-B+Triazole- has shown both antagonism and additive effects 30 .
Investigations are ongoing into the use of a combination of an echinocandin, which as a class is not fungicidal against
Length of Therapy
The following factors should be considered in determining the length of treatment of invasive fungal sinusitis: 1.Complete resolution of all symptoms and signs of the underlying infection for at least two weeks while on antifungal therapy; 2.Near-resolution of radiological findings; 3.Negative cultures; and 4.Reversibility of the underlying risks factors, particularly neutropenia.
Specific clinical infections
Improvement in drug tolerability-----Lipid formulation
Maximal drug prescriptions/duration---Clinical trial
Antifungal drug prophylaxis------------Identify high risk patients
Surgery-----------------------------Debulks the disease and reduces fungal load
Drug discovery------------------------New targets and agents
Dr. Pradipta Kumar Parida Assistant Professor Department of Otorhinolaryngology and Head-Neck Surgery Shri Mahant Indiresh Hospital, Patel nagar, Dehradun, India. Ph. No.-9759471587, e-mail: firstname.lastname@example.org