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Drug Therapy

Indian Pediatrics 1999;36: 1011-1021

Systemic Antifungal Therapy in Pediatric Practice 

R.K. Marwaha and Akhil Maheshwari

From the Department of Pediatrics, Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India.
Reprint requests: Dr. R.K. Marwaha, Additional Professor, Department of Pediatrics, Advanced Pediatric Centre, PGIMER, Chandigarh 160 012.


Fungal infections are being identified with an ever-increasing frequency in immuno- suppressed children, premature infants, patients receiving radiotherapy and/or cytotoxic drugs, and in those with the Acquired Immuno-deficiency Syndrome (AIDS)(1). Simultaneous-ly, there has been remarkable progress in the field of antifungal chemotherapy. The introduc-tion of orally effective drugs with high efficacy, relative safety and broad spectrum activity has permitted outpatient therapy of deep mycoses, long term prophylaxis in immuno-compromised patients and aggressive treatment of even low morbidity conditions. The newer, less toxic formulations of Amphotericin B have also been a major advancement in antifungal chemo-therapy.

The wider choice of antifungal agents that is now available makes it imperative that the practicing physician is familiar with their efficacy, toxicity and interaction patterns with other drugs. This communication briefly reviews these aspects of systemic antifungal therapy in pediatric practice. Table I depicts the salient features of the antifungal drugs presently available and Table II outlines the therapy of specific fungal infectons.

Table I__Antifungal Drugs in Pediatric Practice

Drug    Major Dose Duration Major toxicity interactions
Amphotericin B (AMB) 15-25 mg/kg cumulative (Candidiasis)

Higher (>40 mg/kg) doses with Aspergillosis, Mucor

Depends on maximum  daily tolerate dose

Prolonged, 4-6 wks

Fever, chills, nephrotoxicity, anemia,  GI intolerance   _
5-Flucytosine (5-FC) 50-150 mg/kg divided doses q6h PO Used as an adjunct with AMB Myelosuppresion, GI intolerance, hepatotoxicity AMB reduces excretion  and could increase toxicity
Ketoconazol 3.3-6.6 mg/kg/day, PO Prophylaxis (depending on underlying disorder) GI intolerance, rashes, steroid hormone like action (hypertension, gynecomastia, terfenadine etc.)

H-2 blockers, antacids, phenytoin, rifampin,

Itraconzole 6-10 mg/kg/day, od/2 divisions 2 wks for transient cnadidiasis >4 wks for deeper organ foci/aspergillosis GI intolerance, hepatotoxicity Rifampin, phenytoin, carbamazepine, H-2 blockers
Fluconazole 5 mg/kg/day, od 2-4 wks GI intolerance, rashes Phenytoin, zidovudine, cyclosporine

When to Suspect Fungal Infections?

Broadly speaking, fungal infections should be suspected whenever, in the presence of a predisposing host condition, despite seemingly appropriate antibacterial therapy, the illness continues to have a smouldering, persistent course.

Of all the pediatric mycoses, candidiasis is, by far, the commonest(1). Systemic infection with this yeast is often seen in premature infants, oncology patients who become neutro-penic and other intensive care patients with indwelling central catheters.

In the group of very low birth infants, upto 2-5 per cent can develop systemic candi-diasis(2). In these babies, prolonged antibiotic therapy, intravascular catheters, parenteral nutrition, endotracheal intubation and arti- ficial ventilation are important predisposing factors(3). There are two major forms of systemic candidal infection: the first, with hematogenous dissemination, runs a course characterized by multi-organ involvement, while in the other, with primary renal involvement, the infection remains localized to a single organ(4).

In oncology patients, candidal infections are a significant problem especially in the cases who become neutropenic. The risk of candi-demia increases dramatically after the seventh day of neutropenia(5). Blood cultures, un- fortunately, are notoriously poor at detecting candida in these cases, and are positive in only 5-15 per cent(6). When such infections occur,

the lung, spleen, kidney and liver are involved in more than 50% of all the cases. Fever, chills and gastrointestinal symptoms are the commonest clinical features, while cough, dyspnea, oliguria, azotemia and skin rash may also be seen on occasion(7). It is obvious that most of the clinical features are non-specific, and a high index of suspicion is of utmost importance for the clinician.

Candidiasis is also often seen in patients with indwelling central catheters. Neutropenia, use of broad spectrum antibiotics and hyper-alimentation are again strongly associated(8). In the patients receiving intensive care, the invasive monitoring lines and life support systems provide additional portals of entry, while many of the aforementioned risk factors are already present(9). It is hardly surprising, therefore, that candida would account for 8-15% of all the hospital acquired blood stream infections in certain institutions(10).

Aspergillosis is the second most important group of systemic fungal infectons. More often, this fungus is seen as causing non-invasive (saprophytic) disease like otomycosis or sinunasal infection. It is also known to trigger acute wheezy episodes in asthmatic children, and may even be associated with bronchiectasis in `allergic bronchopulmonary aspergillosis (ABPA)' in children with cystic fibrosis. Invasive aspergillosis, on the other hand, is fortunately limited to the immunocompromized host. It may cause invasive nasosinusitis in neutropenic patients receiving anticancer therapy, fulminant pulmonary infection present-ing as acute penumonia, or may involve other organs to present as endophthalmitis, or as intracranial space occupying lesions (ICSOLs). On rare occasions, it has also been implicated in the causation of osteomyelitis, epidural abscesses, endocarditis, etc.(11).

Cryptococcosis has assumed greater importance with the advent of the HIV   pandemic. It may cause subacute or chronic meningitis, pneumonia, localized infection in the eye, bones or lymph nodes, or present as systemic sepsis(12). Mucormycosis can cause pneumonia or rhinocerebral disease in children with immunodeficiency disorders, and also in diabetics, leukemics and the patients with renal failure. The other infections like Histoplas-mosis, Blastomycosis, Coccidioidomycosis, etc. are extremely rare in our part of the world, and have been referred to briefly in Table II

Table II__Treatment of Specific Fungal Infections

Type of infection Drug of choice Alternatives Duration of therapy
Candidiasis Disseminated infection
  • sick/neutropenic
  • infection with C. glabrata/C. krusei

Disseminated infection 

  • catheter related  primary renal candidiasis 
  • CNS involvement
Amphotericin B  5 flucytosine

 

 


Amphotericin B

Fluconazole      5 flucytosine

 

Fluconazole/ Itraconazole

Fluconazole (may be used as the first line therapy in some centres)

Cumulative dose of 25-40 mg/kg (AMB)

Alternatively, short courses continuing for 10- 14 days after disappearance of signs/symptoms of infection

Aspergillosis Invasive pulmonary/disseminated Hihg dose Amphotericin B  5-Flucytosine Rifampicin Itraconazole (?)1 month or longer
Mucormycosis Amphotericin B in maximum tolerated dose Prolonged therapy for 6 weeks or more
Cryptococcosis  Primary Amphotericin B  + 5-FC Fluconazole   Alternatively low dose AMB (0.3 mg/kg/d)+  5FC (150 mg/kg/d) 6 weeks

6 weeks

Relapses Weekly amphotericin B Depending on recovery from predisposing  condition
Other infections Blastomycosis  Coccidioidomycosis   Histoplasmosis Amphotericin B Itraconazole Prolonged, for months

Drugs Used for Systemic Antifungal Therapy

Amphotericin B (AMB)

AMB was originally discovered nearly seven decades back from an aerobic actino-mycete, Streptomyces nodosus. Till date, it retains its position of being the most effective systemically used antifungal drug. This polyene macrolide antibiotic derives its name from the `amphoteric' behavior of its molecule; the presence of both the carboxyl and the primary amino group confer aqueous solubility at both extremes of pH. It drills pores in the fungal cell membrane by binding to the ergosterol contained therein, and the resulting leakage of the small molecules proves lethal.

(a) Types of Preparations

The original AMB is a complex with the bile salt deoxycholate, marketed as a buffered lyophilized powder in vials of 50 mg each. It forms a colloid in water with particles largely below 0.4 microns in diameter and hence bacterial filters of 0.2 micron pore size are incompatible. The powder should be recons-tituted in 5% dextrose solutions (it precipitates in electrolyte solutions) to a concentration less than 0.2 mg/ml and infused, at least initially, over 4-6 hours (later doses may be infused safely even in 2 h). The infusion bottles need not be covered from light, as was once recommended. Double dose alternate day

The third formulation under trial is the AMB lipid complex (ABLC)(18), which utilizes dimyristoyl conjugates of lecithin and phos-phatidylglycerol. Nephrotoxicity is again claimed to be negligible and doses as high as 5 mg/kg/d have been safely administered(19). The deoxycholate preparation has also been tried in mixture with 20% lipid emulsion (intralipid) in attempts to reduce toxicity, but the results suggest that blood levels and efficacy also fall down(13).

(b) Clinical Uses of AMB

It has useful activity against Candida spp, Aspergilli, Cryptococcus neoformans, the mucormycoses and other deep fungal infec-tions. Some isolates of C. lusitaniae appear to be relatively resistant(13).

A initial test dose of 0.1 mg/kg is prepared in 5% dextrose at a concentration no greater than 0.1 mg/ml and is infused over an hour. Subsequent doses could be of 0.25-0.5 mg/kg and this amount is doubled every 12-24 h time to build up a daily infusion of 1-1.5 mg/kg. Cumulative doses of 15 mg/kg may be adequate for transient candidemia, but larger doses of 25-40 mg/kg are prudent for more sustained cases of systemic candidiasis(1,20). It has been suggested that once the bloodstream is sterilized and there is no other evidence of fungal disease, merely 7-14 additional days of AMB therapy may be adequate for the treatment of candidiasis in children(21).

(c) Alternative Routes of Administration

AMB can also be administered intrathecally in fungal meningitis, especially if the fungus can be demonstrated in the cerebrospinal fluid even after the maximal daily dose in intravenous therapy has been reached. It can be administered in the lumbar sac, into the cisterna magna or into the lateral ventricle either directly or by way of an indwelling reservoir. Such  therapy is, however, only rarely required, and hence the data regarding the ideal intrathecal dose is limited. The initial dose in infants should be 0.01 mg, and may be increased gradually over 5-7 days to 0.1 mg given either every other or the third day. AMB needs to be diluted in sterile water without any bacteriostatic agents and the concentration should not exceed 0.25 mg/ml. Further dilution with CSF is recommended. The complications include CSF pleocytosis (arachnoiditis), transient radiculitis and sensory loss. The adult patients who receive such therapy often complain of headache, and sometimes convulsions may occur(22).

Klein et al. have reported the use of intra-articular AMB in a child with candidal arthritis. They used a single one-time administration of 0.5 mg(23). In ophthalmic practice, intraocular (intravitreal) injections of AMB are now accepted as the standard of care in cases of fungal endophthalmitis(24).

(d) Adverse Effects of AMB

The major acute reaction is fever and chills. Sometimes hyperpnea, stridor or modest hypotension have been observed, but true anaphylaxis is rare. Use of meperidine can shorten such reactions; better still, use of oral paracetamol or intravenous hydrocortisone hemisuccinate 0.7 mg/kg at the start decreases the frequency. These reactions are mediated by IL-1 and TNF, which are released from macrophages and monocytes(13).

Azotemia is another major adverse effect, although it seems to be somewhat less frequent in children than in adults. Although permanent histologic damage to renal tubules has been demonstrated even with short courses, permanent functional defects are extremely rare. Renal tubular acidosis (RTA) and renal wasting of potassium and magnesium may be seen for upto several weeks after therapy. The mechanism of nephrotoxicity has been shown  to be increased intrarenal vascular resistance in experimental animals. Hence, loading with saline to increase effective circulating volume could reduce this damage(25).

Hypochromic, normocytic anemia is usual. The probable mechanism is through a decrease in the production of erythropoietin. Headache, nausea, vomiting, weight loss, phlebitis, ence-phalopathy, thrombocytopenia and leucopenia have all been reported. Cardiac arrhythmias have been seen with acute overdose of AMB which can be countered with hydrocortisone prophylaxis and Verapamil treatment(26).

In view of the toxicity, the patients receiving AMB need to be monitored closely. It may be prudent to look for renal, hematologic and hepatotoxicity by running the tests twice weekly during the course of therapy, once at the end of treatment, and then again 1-2 weeks later. These children also need to be reassessed for relapse of infection within 3 months of successful completion of therapy(27).

AMB has received wide usage in pregnancy as it is not known to have any teratogenic effects(28). Its effect on the fetal organ function is, however, less clear. Dean et al. have reported a neonate whose mother had been treated with AMB during pregnancy and was found to have increased creatinine levels at birth. The placental tissue might have served as a reservoir from which AMB was slowly released into the fetal circulation(29). Yet, although one needs to be cautious while recommending the use of AMB during pregnancy, it still remains the best bet as far the safety of the fetus is concerned. Other antifungals like ketoconazole, flucytosine and griseofulvin have been shown to be teratogenic in animals. Fluconazole, although safe at the usual <150 mg/day doses, may still have some dose-dependent teratogenicity. Itraconzole has been reported to be safe on the basis of anecdotal experience, but the issue still remains to be clarified fully(30).

(e) Combination Therapy

AMB is often combined with 5-Flucytosine (vide infra) in cases with multifocal candidal infection involving the central nervous system, kidneys and the bones/joints. It should be considered especially when the initial response to therapy is poor in the presence of a serious, life-threatening infection, or when there are signs of an impending relapse. With combina-tion therapy, it may be possible to use a lower dose of AMB, and at the same time, it reduces the likelihood of secondary resistance to flucytosine(31). Such combination therapy has also been used successfully in the treatment of cryptococcal meningitis(32).

5-Flucytosine (5-FC)

5-FC is a fluorinated pyrimidine with useful clinical activity against Candida and Crypto-coccus. In adults, it has also been used in chromomycosis.. The susceptible fungi deami-nate it to 5- fluorouracil, a potent antimetabolite which ultimately impairs DNA synthesis. Mammalian cells, which are unable to convert flucytosine to fluorouracil, remain unharmed.

The drug is absorbed well on oral administration. Most of it is excreted (80%) through the kidney. Renal failure, therefore, becomes an indication for plasma level monitor-ing. It penetrates well into the CSF and ocular vitreous(13).

The adverse reactions include bone marrow suppresion and gastrointestinal toxicity. In 5% of the cases, there may be a reversible rise in transaminases. The major clinical problem, if used alone, pertains to emergence of secondary drug resistance, and hence, its use has been limited to an Amphotericin adjunct in Cryptococcal meningitis and sometimes in serious infections caused by Candida(32).

Azoles

The azole antifungals include two broad classes, the triazoles and imidazoles. Triazoles, by virtue of their slower metabolism and higher selectivity for fungal sterol synthesis, are preferred for systemic therapy - notable members being fluconazole and itraconazole. Imidazoles like clotrimazole and miconazole do not have these advantages and therefore have been used mainly as topical agents.

(a) Mechnanism of Action

These agents inhibit sterol 14-alpha- demethylase activity, an enzyme system of the cytochrome P450 group. The synthesis of ergosterol, as a result, gets impaired. The accumulation of 14-alpha-methylsterols dis-rupts the close packing of the membrane phospholipids and thereby interferes with the membrane bound enzymes like the ATPase or the electron transport chain(13).

(b) Clinical Uses of Azoles

Ketoconazole

Ketoconazole(33) is the only imidazole in systemic use. It is effective in candidiasis, various deep mycoses and dermatophytoses. However, the slow response to therapy, variable bioavailability (vide infra) and adverse reactions related to steroid biosynthesis have rendered it somewhat less appropriate for patients with severe or rapidly progressive mycoses. For all its major indications, therefore, the triazole drugs have replaced ketoconazole. Nevertheless, it still holds fort as a prophylactic agent in the immunocompromized patients at risk of fungal infection in oncology or ICU settings.

(i) Pharmacokinetics

Administered orally, the absorption depends on the gastric pH. Its bioavailability, therefore, is reduced when it is prescribed along with H2 blockers or antacids. Ingestion of food, however, does not have a major impact. It undergoes extensive metabolism through the

hepatic cytochrome P450 enzyme CYP 3A4; hence, the list of drug interactions is long - phenytoin and rifampicin reduce its levels while cyclosporine levels get raised, to name a few. There are reports of cardiotoxicity with terfena-dine and astemizole when ketoconazole is being given(34).

(ii) Adverse Effects of Ketoconazole

The adverse effects include a dose dependent GI intolerance, an occasional skin rash or just pruritus. The significant effects are related to inhibition of steroid biosynthesis - menstrual irregularities in the female and gynecomastia and azoospermia in the adult male. Hypertension and sodium-water retention has also been documented. Studies on experi-mental animals also point towards mild hepatotoxicity and tetatogenicity(13).

Itraconazole

Itraconazole, a triazole, is closely related to ketoconazole but offers the advantages of a wider antifungal spectrum and fewer adverse effects. It also covers Aspergillosis besides the candidal infections, sporotrichosis, histoplas-mosis, dermatophytoses and mycetoma forming fungi. Cryptococcosis may respond but is better treated with Amphotericin B or flucona- zole(13,35).

(i) Pharmacokinetics

Itraconazole is administered orally. Blood levels show considerable variability as absorption is lower in the fasting state or with reduced gastric acid. Penetration into CSF and urine is poor although there are claims that the levels attained, howsoever low, are adequate to combat CNS infection. It is almost entirely metabolized in the liver, and the metabolite hydroxitraconazole also has antifungal activity.

(ii) Interactions

Drug concentrations are decreased by  concomitant treatment with rifampicin, phenytoin, carbamazepine and drugs with reduced gastric acidity. It elevates the concen-trations of drugs metabolized through the Cyt P450 CYP 34A including digoxin, cyclosporine and phenytoin. It may also precipitate cardio-toxicity of terfenadine and astemizole(36).

(iii) Adverse Effects

Adverse effects are seen only occasionally with Itraconazole. These include GI intolerance, hypertriglyceridemia, hepatotoxicity, hypokale-mia and rash. At higher doses, adrenal insufficiency, lower limb edema, hypertension, and in one patient, rhabdomyolysis have been reported(37).

Fluconazole

Fluconazole, another triazole, differs from itraconazole in a few important aspects(38).

(i) Pharmacokinetics

Fluconazole is almost completely absorbed on oral adminstration, and food or gastric acidity do not affect absorption. It is almost totally (90%) excreted through the kidneys and hence, offers a therapeutic advantage in renal involvement. CSF penetration is also higher (50-90%). It has, therefore, been used in cryptococcal meningitis in the HIV positive patients with success.

(ii) Interactions

Fluconazole raises the levels of phenytoin, zidovudine, cyclosporine but causes little alteration in theophylline levels. It also seems to be less prone to raise terfenadine levels. The interactions with rifampicin are also clinically insignificant.

(iii) Adverse Effects

The adverse effects are all quite uncommon; GI intolerance, skin rash/Steven Johnson

syndrome, alopecia, hepatotoxicity have all been observed in <2% of patients.

(iv) Clinical Uses

It has been extensively used in candidiasis(38), including systemic infections, as well as in involvement of the esophagus, kidneys, or other deeper organs. A mean dose of 3.4-5.3 mg/kg/d for 26 - 36 days showed a 73-97% response in cases which were refractory to treatment with conventional agents(38). Treatment of mucosal candidiasis with fluconazole has shown a higher efficacy than ketoconazole and other polyenes in immunocompromized patients. It may not be effective for treatment in profoundly neutro-penic cases(39) but at the same time it has been used successfully for prophylaxis in oncology and ICU settings. It is the drug of choice for secondary prevention after treatment of cryptococcal meningitis in AIDS cases(38); for milder disease with favorable prognostic signs, it has even been used as the first line therapy. Fluconazole has comparable activity against coccidioidomycosis, histoplasmosis, blasto-mycosis, ringworm and sporotrichosis

It, however, does not have activity against aspergilli. Like other azoles, it also does not work against Candida krusei isolates and in mucormycosis.

Griseofulvin

Griseofulvin has proven to be effective against a wide range of dermatophytes like the trichophytons, epidermophytons and the micro-sporons. It, however, is ineffective against candida or the other fungi causing deep mycoses. It acts by inhibiting the fungal mitosis by interacting with the microtubules and thereby disrupting the mitotic spindle.

The dosage is 15-20 mg/kg/day of the microcrystalline preparation, upto a maximum of 1 g/day, in divided doses. The treatment,  however, needs to be continued for relatively prolonged periods. Cutaneous infections may need 3-6 weeks while infections involving the nails may have to be continued for 6-18 months. The compliance, therefore, often becomes a major issue.

The adverse effects include headache, peripheral neuritis, lethargy, mental confusion, fatigue, skin rashes, and rarely, bone marrow suppression or mild reversible nephrotoxicity. It may raise porphyrin levels in the patients with porphyria(13).

With the relatively larger choice of antifungal agents available today, the outlook has improved vastly in pediatric fungal infec-tions. Most of the published reports on large series of patients include adults who often have underlying serious illnesses affecting the outcome directly. The prognosis for children on antifungal therapy may actually be much better, in terms of both the figures of survival and the incidence of adverse effects(1).

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