Sei sulla pagina 1di 9

SPECIAL FOCUS y Invasive pediatric fungal infections

Review

www.expert-reviews.com/toc/eri/9/3

Caspofungin therapy in immunocompromised children and neonates Expert Rev. Anti Infect. Ther. 9(3), 347–355 (2011)

Caspofungin therapy in immunocompromised children and neonates

Expert Rev. Anti Infect. Ther. 9(3), 347–355 (2011)

Ayper Somer 1 , Selda H Törün 1 and Nuran Salman 1

1 Istanbul University, Istanbul Medical Faculty, Department of Pediatric Infectious Diseases, Millet Cad. 34390 Capa, Istanbul, Turkey Author for correspondence:

Tel.: +90 212 414 2000/31298 Fax: +90 212 621 5373 ayper.somer@gmail.com

The prevalence of invasive fungal infections is increasing and the infections are becoming a major problem in immunocompromised children and neonates. Fortunately, there has been a recent surge in the development of new antifungal agents. Caspofungin, the first licensed echinocandin, is a novel class of antifungal and is approved for use in children 3 months of age or older for the treatment of invasive candidiasis, salvage therapy for invasive aspergillosis and as empirical therapy for febrile neutropenia. This article reviews the published data on the use of caspofungin in immunocompromised children and neonates with invasive fungal infections.

KEywOrdS: antifungal therapy • Aspergillus infections • Candida infections • echinocandin • fungal infections • neonates

In the past two decades, there has been a con- siderable increase in both the frequency and importance of invasive fungal infections in pediatric hospitals. Premature neonates, patients that were admitted to intensive care units, and immunocompromised children with under- lying malignancies or undergoing stem cell or solid organ transplantation are at high risk for invasive fungal infections [1–4] . In response to the increased incidence and high mortality rates, novel antifungal agents have been devel- oped to expand the breadth and effectiveness of treatment options available to clinicians. Echinocandins are the latest family of drugs that have been shown to be both safe and effec- tive in the treatment of invasive fungal infec- tions. Caspofungin, the first licensed member of this class of antifungals, has been approved for primary treatment of esophageal candidia- sis and candidemia, for second-line therapy of invasive aspergillosis and for empirical anti- fungal therapy in adults [5–9] . The compound received US FDA approval in July 2008 for use in children 3 months of age or older, as first- line therapy for empirical treatment in patients with fever and neutropenia, invasive Candida infections, esophageal candidiasis and as salvage therapy for invasive aspergillosis [10] . This arti- cle summarizes the pharmacology, pharmaco- kinetics and clinical studies of caspofungin in the pediatric population and discusses its role in

the pediatric antifungal armamentarium, focus- ing on the more recent data surrounding this antifungal agent.

Mechanism of action

Caspofungin, similar to other echinocandins, is

a semisynthetic amphiphilic lipopeptide, struc-

turally characterized by a cyclic hexapeptide core-linked lipid side chain. Caspofungin acts by noncompetitive inhibition of the synthesis of the polysaccharide 1,3-b-d- glucan, which is present in the cell wall of many pathogenic fungi, but is absent in mammalian cells. This molecule plays an important role in the osmotic integrity of the fungal cell as well as in maintaining cell division and growth [11–13] . By inhibiting the formation of this molecule, caspofungin compromises fun- gal cell wall integrity and renders fungal cells more susceptible to cell death.

Antifungal activity & pharmacodynamics

Caspofungin demonstrates a species-dependent

mode of antifungal activity. In vitro, caspofungin

is fungicidal against Candida spp., but fungistatic

against Aspergillus spp. [14–16] . The compound exerts concentration-dependent, fungicidal activ- ity and prolonged post-antifungal effects against most Candida species [17–19] . Caspofungin activity has been best characterized against Candida spe- cies. A large study analyzing 5346 global Candida isolates collected from 2001 to 2006 indicates

www.expert-reviews.com

10.1586/ERI.11.4

© 2011 Expert Reviews Ltd

ISSN 1478-7210

347

Review

Somer, Törün & Salman

Table 1. Activity profile of caspofungin against clinically important species of Candida and Aspergillus .

Organism

MIC 50 (µg/ml)

MIC 90 (µg/ml)

Candida albicans

0.03

0.06

Candida tropicalis

0.03

0.06

Candida glabrata

0.03

0.06

Candida parapsilosis

0.25

1

Candida krusei

0.12

0.25

Candida lusitaniae

0.25

0.5

Candida guilliermondii

0.5

1

Aspergillus fumigatus

MEC: 0.5–1

Aspergillus flavus

MEC: 0.5–1

Aspergillus terreus

MEC: 0.5–2

MEC: Minimum effective concentration. Data taken from [20,21,23] .

 

that caspofungin is active against a wide range of Candida spp. in vitro (Table 1) [20] . The MICs of Candida parapsilosis and Candida guilliermondii were up to 100-fold higher than other species, which may be of particular concern because C. parapsilosis is an impor- tant pathogen in many pediatric infections [20,21] . The basis of this resistance is not clearly understood. Clinical data obtained from adults did not confirm this hypothesis and patients with invasive C. parapsilosis infections were treated successfully with caspofungin [5–7] . Similarly, in a retrospective study involving neonates, inva- sive candidiasis due to C. parapsilosis was effectively treated with caspofungin, although in vitro data suggested lower activity of the compound against this pathogen [22] . In vitro antifungal activity of caspofungin against Aspergillus spp. (Table 1) has typically been described in terms of minimum effective concentration (MEC) based on morphologic changes on microscopy rather than MICs [23–25] . Microscopical examination of drug-exposed A. fumigatus shows dose-dependent damage of Aspergillus colonies with swollen hyphal elements that appear to be cell wall deficient but are able to regain their cell walls in the absence of drug [26] . Caspofungin also has variable activity against other fungal species. It has very little or no activity against Zygomycetes, Cryptococcus, Fusarium or Scedosporium [16,27–29] . The com- pound has some activity against Blastomyces, Penicillium and Pneumocystis species, but there is little clinical evidence to support these in vitro data [21,30] . Given its unique mechanism of action, caspofungin has been studied in different antifungal combina- tions. In all combinations tested, no evidence of antagonism has been demonstrated [10,31] .

Resistance

As expected from its mechanism of action, caspofungin lacks cross-resistance to other classes of antifungal agents. Since caspofungin does not penetrate into the cytoplasm of the fungal cells, resistance mechanisms described for azoles such as efflux

pumps and alterations in sterol composition are not expected [17] . Resistance to echinocandins in otherwise susceptible fungal yeast species is rare: but mutations in the FKS1 and FKS2 genes have been identified as a possible mechanism for caspofungin resistance [11,32] . These genes encode protein subunits that make up 1,3-b-d- glucan synthase. There have been reports of emerging Candida strains, especially Candida albicans and Candida glabrata isolates, that have elevated MICs correlating with clinical treat- ment failure following caspofungin exposure [33–35] . FKS1-mutant Candida strains resistant to caspofungin are also found to be resistant to micafungin and anidulafungin [36] . Little is known about potential mechanisms of echinocandin resistance among Aspergillus spp. [37] . Development of resistance to caspofungin in Aspergillus spp. in vitro has not been reported [10] . A group of studies have shown that high caspofungin concentrations may paradoxically reduce antifungal activity against Candida and Aspergillus [23,38–40] . However, this paradoxical effect does not appear to be related to resistance mechanisms or upregulation, but may in fact be a laboratory-related phenomenon without clinical relevance [36] .

Pharmacokinetics

Caspofungin has poor oral bioavailability and requires intra- venous administration. The compound is highly protein bound to albumin (97%) and distributes to all major organ sites. In a murine study, caspofungin tissue levels were higher than serum levels in the liver, kidney and large intestine, lower in the heart, brain and thigh, and similar in the lung and spleen [41] . CNS involvement is of particular concern in neonates and premature infants with disseminated candidiasis [42] and potentially poor penetration of caspofungin in cerebrospinal fluid reported in one study could suggest that this compound is less desirable in the setting of CNS infections [43] . In adults, the compound has linear plasma pharmacokinetics and a b-phase half-life of 10–15 h, thus allowing for once-daily dosing [41,44,45] . Caspofungin is thought to chemically degrade in tissue and blood to an inactive structure and is metabolized by the liver via hydrolysis and N-acetylation, and slowly excreted into urine and feces. Only small fractions (<2%) of a dose are excreted into urine in an unchanged form [45,46] . The com- pound is not dialyzable and no dosage adjustment is required in patients with renal insufficiency or mild hepatic failure. The clearance of caspofungin is modestly reduced in subjects with moderate hepatic insufficiency (Child–Pugh score of 7–9) and a reduction from the usual daily dose of 50–35 mg/day is recom- mended in adults [30] . In adults, caspofungin is administered as a loading dose of 70 mg followed by a daily maintenance dose of 50 mg [47] . The pharmacokinetics of caspofungin were evaluated in children and adolescents as well as in neonates. The first pediatric caspo- fungin pharmacokinetic study was performed by Walsh et al. in 39 children (aged 2–11 years) and adolescents (aged 12–17 years) with neutropenia, and a comparison of weight-based or a body surface area regimen was made [48] . Patients received caspofungin at 1 mg/kg/day or 50 mg/m 2 /day and plasma pharmacokinetics

Caspofungin therapy in immunocompromised children & neonates

Review

were evaluated on days 1 and 4 at 0, 1, 2, 4, 8, 12 and 24 h after the start of infusion. The first cohort (nine children) receiving caspofungin at a dose of 1 mg/kg once daily had a faster clear- ance of the compound with lower serum concentrations com- pared with those achieved with typical doses in adults. Serum concentrations were observed to be weight- and age-related [49] .

Therefore, the subsequent cohort of 18 pediatric patients received

a dose of 50 mg/m 2 once daily. This body surface area-based dos-

ing (50 mg/m 2 /day) showed no statistically significant variation from adult patients in caspofungin AUC 024 and plasma clearance, suggesting that this may be an appropriate dosing regimen for pediatric patients [48] . Pharmacokinetic parameters were generally lower than those for adults and caspofungin levels tended to be lower in younger, smaller children than in older, larger children (Table 2). Additionally, b-phase half-life was reduced 32–43% in children relative to adults. No serious drug-related adverse events occurred in association with caspofungin treatment. A recently published prospective pharmacokinetic study eval- uated nine children 10–22 months of age with febrile neutro-

penia [50] . In this study, patients received caspofungin at a dose of 50 mg/m 2 /daily and drug concentrations were similar to that of adults receiving 50 mg/day, suggesting similar plasma expo- sure. Based on these data, subsequent dosing in children has been proposed to be a loading dose of 70 mg/m 2 followed by daily maintenance dosing of 50 mg/m 2 . Similar findings were observed in neonates and infants up to 3 months of age (12 neonates with

a gestational age of 24–41 weeks; chronological age 1–11 weeks)

given 25 mg/m 2 /day [43] . No patients developed drug-related adverse events or discontinued caspofungin owing to toxicity. The pharmacokinetic analyses suggested that caspofungin at a dose of 25 mg/m 2 once daily provides similar plasma concentra- tions to that in adults receiving 50 mg daily. Caspofungin is not recommended for use in neonates or infants less than 3 months of age, but the dosage of 25 mg/m 2 once daily seems reasonable for this group of patients, including low-birth-weight and extremely low-birth weight infants [10,43] .

Drug interactions

Caspofungin is not a substrate of the cytochrome P450 enzyme system or the intestinal glycopeptides and has few drug inter- actions [13,30] . Clinical studies have shown that the pharma- cokinetic properties of caspofungin are not altered by itracona- zole, amphotericin B, mycophenolate, nelfinavir or tacrolimus. Caspofungin coadministration reduces tacrolimus levels by approximately 20% and dose adjustments may be required, but has no effect on cyclosporine levels [10,30] . However, cyclosporine increased caspofungin levels by 35% and transient elevations of hepatic transaminases in healthy volunteers have been observed. As a consequence, concomitant usage of caspofungin and cyclosporine should be limited to patients for whom the poten- tial benefit outweighs the potential risk [10,30,51] . Inducers of drug clearance, such as efavirenz, nelfinavir, nevirapine, pheny- toin, rifampin, dexamethasone and carbamazepine, may reduce caspofungin concentrations and an increase in the daily dosage to 70 mg should be considered [10] .

Side effects

Adverse reactions with caspofungin have overall been infrequent and minor. Caspofungin does not seem to be significantly hepato- toxic or nephrotoxic. Like other basic polypeptides, caspofungin has the potential to cause the release of histamine [52–55] . In adult studies, the primary adverse effects were fever, headache, vomit- ing and diarrhea, signs of histamine release such as rash, facial swelling, pruritus or a sensation of warmth, anaphylactic reactions and irritation at the injection site [30,52] . In a study conducted by Groll et al. including 64 pediatric patients, 53.1% of chil- dren receiving caspofungin therapy experienced mild or moder- ate adverse events [56] . The most frequent side effects were fever, nausea and vomiting, diarrhea, headache and skin eruption. Mean hepatic transaminase values were slightly elevated at the end of treatment, but caspofungin was not discontinued in many of the patients. An analysis of the safety data from five prospective pedi- atric clinical studies was published by Zaoutis et al. [57] . A total of 197 patients were enrolled in these studies and 171 patients (age range: 1 week to 17 years) that received at least one dose of caspofungin were evaluated. The median duration of treatment was 9 days (range: 1–87 days). The incidence of drug-related clinical and laboratory adverse events in children receiving caspo- fungin was 26 and 16%, respectively. The most common adverse effects were fever (12%), elevation in transaminases (8%), rash (5%) and a decrease in serum potassium (4%). In two patients (1%), caspofungin therapy was discontinued because of a drug- related adverse event: moderate hypotension in one patient and a moderate rash in the other. There is the potential for elevations in liver function tests with caspofungin treatment. The US prescribing information recommends monitoring for evidence of worsening hepatic function among patients who develop abnormal liver function

Table 2. Pharmacokinetic parameters of caspofungin and dosing regimens for children 2–17 years of age.

Parameter

Pharmacokinetic properties of caspofungin

Volume of distribution

No data

Clearance (mean values)

5.2–8.6 ml/min/m 2

Half-life (mean values)

8.2–16.5 h

Metabolism

Hydrolysis and N-acetylation

Elimination

35% feces, 41% urine (1.4% unchanged)

Drug interactions

Cyclosporine, rifampin, tacrolimus and selected inducers of clearance

Dosing

70 mg/m 2 loading dose, followed by

50

mg/m 2 /day; 25 mg/m 2 /day in

neonates

Dose adjustment

Moderate hepatic insufficiency; 70 mg loading dose (if appropriate), then

35

mg daily

Data taken from [10,48,50] .

Review

Somer, Törün & Salman

test results [10] . This recommendation is based on preclini- cal data obtained from studies on micafungin, another echino- candin. At very high doses of micafungin, liver tumors were observed in rats, which was dependent on both dose and dura- tion of treatment [58] . This phenomenon was not demonstrated during caspofungin treatment.

Indications & approval status for pediatric patients

Caspofungin is the first echinocandin approved by the FDA in January 2001, for primary treatment of esophageal and invasive

candidiasis, invasive aspergillosis not responding or intolerant to other antifungal therapies, and for empirical antifungal therapy in febrile neutropenia in adults. After the favorable results obtained from several retrospective analyses and two prospective clinical trials, caspofungin received approval for use in children 3 months

of age and older in July 2008 from the FDA. In this age group, the

compound is approved as first-line therapy for empirical treatment

in patients with fever and neutropenia, invasive Candida infections,

esophageal candidiasis and as salvage therapy for invasive aspergil-

therapy, either as monotherapy or in combination, mostly with amphotericin B and/or voriconazole. Nine patients experienced drug-related adverse events, but caspofungin was not discontin- ued in many of the patients. Complete response to caspofungin therapy was achieved in five of seven patients with antifungal

combination while salvage therapy rescued eight of 13 children.

A multicenter retrospective survey investigated the efficacy

of caspofungin in various invasive fungal infections occurring in 64 severely immunocompromised pediatric patients (median

age: 11.5 years; range: 0.4–17.9 years) [56] . The mean duration of caspofungin therapy was 37 days (range: 3–128 days) and

23 patients were diagnosed with aspergillosis and eight were diag-

nosed with candidiasis. Caspofungin was used as monotherapy in 20 patients and in combination with other antifungals in

44 patients. Complete and partial responses were obtained in

61% of patients with proven or probable invasive fungal infection.

A retrospective review of children who received caspofungin as

empirical therapy for fever and neutropenia showed that 79% of caspofungin courses resulted in an overall favorable response [51] .

losis [10] . The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) gave a posi- tive review for the use of caspofungin in the pediatric population in September 2008. Caspofungin is currently not approved for use in neonates and infants up to 3 months of age. Micafungin has been licensed for use in children and neonates in Europe since April 2008, but is not yet approved for children in the USA [58] .

In this study including 56 patients (median age: 8 years; range:

1–17 years), seven children had proven fungal infections at base- line and four (57%) of these resolved while receiving caspofungin therapy. Therapy was halted in 13% of cases because of thera- peutic failure or adverse drug events, none of which were directly attributed to caspofungin. The most common adverse events were rash and hypokalemia. Hepatotoxicity was reported in only one of 19 patients who received concomitant cyclosporine therapy. Several case reports [62–65] and retrospective studies [56,59–61,66] have described caspofungin use for a variety of fungal infections in pediatric patients, but there are only two prospective open-label studies published in this area. The first prospective, open-label, randomized, double-blind, multicenter, noncomparative efficacy and safety trial of caspofun-

gin in pediatric patients was conducted by Zaoutis et al [67] . In this study, 49 patients (age range: 3 months to 17 years) with invasive aspergillosis, invasive candidiasis or esophageal candidiasis were treated with caspofungin administered as 50 mg/m 2 daily after a

Caspofungin studies in immunocompromised children & adolescents

The first caspofungin study in immunocompromised children was

a

retrospective study and evaluated the safety of the compound [59] .

total of 25 immunocompromised pediatric patients (median age:

9.8 years; range: 0.3–26.2 years) received caspofungin for various indications for a median duration of 32 days (range: 1–116 days)

A

dosages of 0.8–1.6 mg/kg/day for patients weighing 50 kg and

50–75 mg for patients weighing greater than 50 kg. All 21 patients with documented or suspected infection also received liposomal amphotericin B, but three patients also received itraconazole and three also received voriconazole. Only three patients (12%) expe- rienced drug-related adverse events and caspofungin was not pre- maturely discontinued in any patients. Patients included in the study were treated with antifungal combination therapy, therefore no effectiveness data could be obtained from the study. The first prospective caspofungin trial in pediatric patients was conducted by Walsh et al. as a Phase I/II dose-finding study. None of the patients developed a serious drug-related adverse event or discontinued treatment because of toxicity [48] . Initial clinical efficacy studies of caspofungin in children were limited to refractory cases of invasive candidiasis and as

salvage or combination therapy in aspergillosis (Table 3) [60,61] . In

at

70

mg/m 2 loading dose. A favorable response was seen in 30 out of

37

(81%) patients with invasive candidiasis and in one patient with

esophageal candidiasis; caspofungin was given as primary therapy in the majority of the cases. Caspofungin was given as salvage therapy to the patients with aspergillosis and a favorable response was seen in five out of ten (50%) of these patients. Drug-related clinical or laboratory adverse events occurred in 27 and 35% of patients, respec- tively. Most drug-related clinical adverse events were mild and none led to therapy discontinuation. The most common drug-related

laboratory adverse events were increased hepatic transaminase levels.

 

A

multicenter, randomized, double-blind study investigated

the efficacy of caspofungin (70 mg/m 2 loading dose on day 1, then 50 mg/m 2 daily) for empiric therapy in 82 children aged 2–17 years with persistent fever and neutropenia, with liposomal amphotericin B (3 mg/kg daily) as the comparator agent [68] . Caspofungin was found to be at least as effective as liposomal amphotericin B (46.4 vs 32%, respectively) in overall treatment. Serious drug-related adverse events occurred in 1.8% of the

a

retrospective study, conducted as part of the Compassionate

Use French Program, 20 children (median age: 12 years; range:

0.1–16 years) with proven or probable invasive fungal infection received caspofungin therapy [60] . Patients with aspergillosis and candidiasis were treated with caspofungin as first-line or as salvage

Caspofungin therapy in immunocompromised children & neonates

Review

Table 3. Caspofungin clinical data in immunocompromised children.

 

Study

Study

Patients

Age (years)

Indication for therapy with

Outcomes

Ref.

(year)

characteristics

(n)

caspofungin (n)

Franklin et al.

Retrospective

25

0.3–26.2

Prophylaxis (4), suspected (8) and proven (13) IFI

No efficacy data obtained

[59]

(2003)

 

Cesaro et al.

Retrospective

10

6–24

Salvage therapy for possible (1), probable (6) and proven (3) IFI Combination with L-AMB

Favorable response: 55.6%

[79]

(2004)

 

Merlin et al.

Retrospective

20

0.1–16

Probable (8) and proven (12) IFI

Complete response: 65% Partial response: 20% Successful response: eight out of 11 (aspergillosis), four out of seven (candidiasis)

[60]

(2006)

Groll et al.

Retrospective

64

0.4–17.9

Empiric therapy (16), possible (17), probable (14) and proven (17) IFI

Therapy response: 67.7% Overall survival: 70% at 3 months post-treatment

[56]

(2006)

Koo et al.

Retrospective

56

1–17

Empiric therapy for febrile neutropenia

Favorable response: 79% Fever resolution: 85%

[51]

(2007)

Cesaro et al.

Retrospective

40

1.2–17.9

Combination therapy for invasive aspergillosis

Favorable response: 53% Failure: 5%

[61]

(2007)

Zaoutis et al.

Prospective,

49

3 months–17 years

Proven IFI (48)

Favorable response:

[67]

(2009)

open-label

candidiasis: 81%;

 

aspergillosis: 50%

Maertens et al. (2010)

Double-blind,

82

2–17

Persistent fever and neutropenia (all 82)

Favorable response: L-AMB:

[68]

randomized with

32%; caspofungin: 46.4%

 

L-AMB

IFI: Invasive fungal infection; L-AMB: Liposomal amphotericin B. Adapted from [54] .

 

patients receiving caspofungin at the currently recommended dosage and in 11.5% of the patients receiving amphotericin B. Evaluation of effectiveness on breakthrough infections, post-ther- apy survival, discontinuation of study drug and fever resolution showed that caspofungin treatment was as (if not more) effective as liposomal amphotericin B treatment. With the increase in the antifungal treatment options, pre- scription and treatment strategies have changed significantly. A retrospective cohort study from 2000 to 2006, in 25 freestanding children’s hospitals in the USA showed these changes [69] . In this period, a total of 62,842 patients received antifungal therapy and the most commonly prescribed antifungal agent was flu- conazole (76%), followed by amphotericin preparations (26%). Caspofungin prescription significantly increased for the treatment of disseminated/systemic candidiasis, from 0% in 2000–2001 to 23% in 2005–2006. The increase in caspofungin utilization is not surprising since the data from prospective pediatric efficacy and safety studies showed that caspofungin is at least as effective as amphotericin B for the treatment of candidiasis and its use is associated with fewer side effects [67,68] .

Caspofungin use in neonates

Caspofungin is not approved for use in neonates and children below 3 months of age but there is growing experience in this group of patients (Table 4). The first reported use of caspofungin was in an

extremely low-birth-weight neonate born at 24 weeks of gestation who developed a systemic Candida guilliermondii infection in the second week of life [70] . Caspofungin failed to control this invasive fungal infection but no side effects of the drug were observed. After this first report, experience with caspofungin in neonatal candidiasis was reported in a retrospective case series of ten children (one term and nine preterm neonates; mean gestational and chron- ologic age 33 weeks and 44 days, respectively) treated in a Costa Rican neonatal intensive care unit [22] . Six patients had persistently positive peripheral blood cultures after central catheter removal and two patients progressed to disseminated disease, and all neonates had failed prior treatment with amphotericin B and/or fluconazole. In all patients, amphotericin B was discontinued and caspofungin was initiated at a dosage of 1 mg/kg/day for 2 days followed by a once-daily dose of 2 mg/kg. All eight patients with persistent candidemia had infection clearance between 3 and 7 days after initiation of caspofungin. One child with candidemia had a relapse but responded to a second course of caspofungin and one patient died from bacterial sepsis. No adverse drug events were observed. Results from another retrospective chart review were less favora- ble with lower dosing of caspofungin (1 mg/kg/day) in 13 neonates (median gestational age: 27 weeks; range: 24–48 weeks) who were refractory to amphotericin B or fluconazole or flucytosine therapy [71] . Sterilization of blood cultures was achieved in 11 of the 13 children after 3 days (range: 1–21 days) of caspofungin therapy.

Review

Somer, Törün & Salman

Table 4. Caspofungin clinical data in neonates and children up to 3 months of age.

 

Study (year)

Study

Patients

Age (n)

Indication for therapy

Outcomes

Ref.

characteristics

(n)

with caspofungin

Natarajan et al.

Retrospective

13

1 term, 12 preterm (mean gestational age: 27 weeks)

Refractory candidemia

Blood culture sterilized in 11 out of 13; two failures occurred with Candida albicans

[71]

(2005)

Odio et al.

Retrospective

10

1 term, 9 preterm (mean gestational age: 33 weeks)

Refractory invasive

8 out of 8 with persistent candidemia resolved only with caspofungin

[22]

(2004)

candidiasis

Odio et al.

Retrospective

36

9 term, 31 preterm (mean gestational age: 34 weeks)

Refractory invasive

All patients were effectively treated

[72]

(2007)

candidiasis

Sáez-Llorens et al. (2009)

Prospective

18

24–41 weeks

Documented or highly suspected candidiasis

No efficacy data obtained

[43]

Adapted from [54] .

Two children died from candidemia but only five of 13 patients sur- vived without reoccurrence. Treatment was well tolerated; adverse events included thrombophlebitis in one patient, hypokalemia in two patients and elevation of liver enzymes in four patients. Another trial reported 36 neonates (mean gestational age:

34 weeks) treated with caspofungin for invasive candidiasis refrac- tory to amphotericin B [72] . Caspofungin was given as mono- therapy at a dosage of 2 mg/kg/day for extrameningeal infection and 3 mg/kg/day for meningitis. All patients were effectively treated and no clinical or laboratory adverse events were detected. Two case reports imply that dosing around 3 mg/kg may be needed for the treatment of candidiasis in neonates, but higher doses (>5 mg/kg) could result in major toxicities [73,74] . While these case series are encouraging, larger prospective and comparative studies are needed to determine the role of caspo- fungin in neonatal candidiasis and the optimal dose to use in this population.

Caspofungin use as combination therapy

Given the substantial mortality and morbidity related to invasive fungal infections, treatment with a combination of antifungal agents is often considered. Caspofungin has a different mode of action compared with other antifungal compounds and, at least theoretically, could be included in all combination models. Several case reports [64,75–78] and clinical studies [61,79] demon- strated rapid clinical improvement after caspofungin was added to antifungal therapy. In a smaller prospective, open-label study, ten pediatric cancer patients (median age: 13 years; range: 6–24 years) suffering from invasive fungal infection that failed to improve or even progressed on empiric antifungal therapy received caspofungin as rescue therapy [79] . Response to combination therapy with caspofun- gin and liposomal amphotericin B was evaluated in nine patients who had received rescue therapy for at least 7 days. Five of these patients had a complete response, three had stable disease and rescue therapy failed in one patient. Combination therapy was well tolerated. The most common side effect was hypokalemia (80%) and thrombophlebitis in two patients. The authors suggested

that combination antifungal therapy could be used in severely ill patients with refractory invasive mycosis without causing significant drug toxicities. The larger caspofungin-based combination therapy study was a review of 40 children enrolled in an Italian hematology oncology registry that collected data on antifungal combination therapy for invasive aspergillosis [61] . Most patients had severe neutrope- nia at diagnosis and 39 had pulmonary infections. A total of 33 (82.5%) children received antifungals before beginning caspo- fungin in combination with either voriconazole or liposomal amphotericin B. The combination therapy was well tolerated and a favorable response to antifungal therapy was achieved in 53% of patients. The authors concluded that caspofungin com- bination therapy was comparably as effective in children with invasive aspergillosis at high risk as first-line monotherapy with voriconazole or liposomal amphotericin B [21] . In another study conducted in extremely low-birth-weight neonates suffering from persistent central venous catheter-related candidemia, caspofungin and liposomal amphotericin B com- bination therapy was successful and catheter removal was not needed for rescue from candidemia [80] . The efficacy of caspofungin as combination therapy has not yet been evaluated in prospective trials and further studies are needed to investigate the benefits of caspofungin used in combination for pediatric invasive mycosis, both as primary and salvage therapies.

Expert commentary & five-year view

Over the past decade the incidence of invasive fungal infections has increased in the pediatric population and there is a need for well-tolerated antifungal drugs with a broad spectrum of activity. In that respect, the development of the class of echinocandins may be considered as a milestone in antifungal chemotherapy. Of the echinocandins, caspofungin is the first agent approved for use in children 3 months of age and older. In pediatric patients, caspofungin is licensed for first-line therapy of invasive candidia- sis, for empirical therapy of patients with neutropenic fever and suspected fungal infections, and for salvage treatment of invasive aspergillosis. The last 5 years of experience with caspofungin in

Caspofungin therapy in immunocompromised children & neonates

Review

pediatric patients indicates the absence of fundamental differ- ences in type and frequency of adverse effects relative to adults and suggests similar therapeutic effectiveness. Several retrospective analyses and two prospective clinical trials confirm the excellent safety profile of caspofungin in children. Pediatric dosing regi- mens and pharmacokinetics of caspofungin are well established. However, further research is required to establish pharmacoki- netics and dosing in preterm and term neonates. Caspofungin may play a role in combination therapy. Combination therapy cannot currently be recommended as a routine first-line strategy in patients with invasive fungal infections. However, it may be useful against invasive aspergillosis in stem cell transplant recipi- ents, patients with chronic neutropenia or patients with CNS or

disseminated infections. More large-scale, prospective controlled trials are needed to clearly define the efficacy, safety and role of caspofungin in combination, for the management of pediatric fungal infections.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues

Caspofungin, the first licensed echinocandin, acts by noncompetitive inhibition of 1,3-b- d - glucan synthesis in the fungal cell wall.

The compound has broad-spectrum activity against Candida and Aspergillus species, favorable pharmacokinetics and an excellent safety profile.

Caspofungin is approved for primary treatment of esophageal candidiasis and candidemia, for second-line therapy of invasive aspergillosis and for empirical antifungal therapy in patients 3 months of age or older.

In pediatric patients, a body surface area-based dosing with a loading dose of 70 mg/m 2 /day followed by 50 mg/m 2 /day appears to result in therapeutic plasma concentrations.

Use in neonates less than 3 months of age is not recommended as first-line therapy; further studies are needed for the neonatal population.

Several small trials in pediatric patients have been conducted to examine the effectiveness of caspofungin against invasive fungal infections and have suggested similar therapeutic efficacy as in adult patients.

Caspofungin may also prove to be valuable as part of combination therapy for invasive aspergillosis.

Although caspofungin exhibits an excellent safety profile, adverse events may include fever, headache, rash, flebitis and transient elevations of liver transaminases.

References

Papers of special note have been highlighted as:

• of interest

•• of considerable interest

1 Steinbach WJ, Walsh TJ. Mycoses in pediatric patients. Infect. Dis. Clin. North Am. 20, 663–678 (2006).

2 Dvorak CC, Steinbach WJ, Brown JM, Agarwal R. Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 36, 621–629 (2005).

3 Groll AH, Lerhrnbecher T. New antifungal drugs and the pediatric cancer patient: current status of clinical development. Klin. Pediatr. 217, 158–168

(2005).

4 Castagnola E, Bagnasco F, Faraci M et al. Incidence of bacteremia and invasive mycoses in children undergoing allogeneic hematopoietic stem cell transplantation: a single center experience. Bone Marrow Transplant. 41, 339–347 (2008).

5 Villanueva A, Arathoon EG, Gotuzzo E et al. A randomized double-blind study of

caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin. Infect. Dis. 33, 1529–1535 (2001).

6 Villanueva A, Gotuzzo E, Arathoon EG et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am. J. Med. 113, 294–299 (2002).

7 Mora-Duarte J, Betts R, Rotstein C et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N. Eng. J. Med. 347, 2020–2029 (2002).

8 Maertens J, Raad I, Petrikkos G et al. Caspofungin Salvage Aspergillosis Study Group. Efficacy and safety of caspofungin for the treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin. Infect. Dis. 39, 1563–1571

(2004).

9 Walsh TJ, Teppler H, Donowitz GR et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N. Eng. J. Med. 351, 1391–1402 (2004).

10 Product information. Cancidas (caspofungin). Merck and Co., Whitehouse Station, NJ, USA (2009).

11 Kurtz MB, Douglas CM. Lipopeptide inhibitors of fungal glucan synthase. J. Med. Vet. Mycol. 35, 79–86 (1997).

12 Georgopapadakou NH. Update on antifungals targeted on the cell wall: focus on b-1,3-glucan synthase inhibitors. Expert Opin. Investig. Drugs 10, 269–280 (2001).

13 Denning DW. Echinocandin antifungal drugs. Lancet 362, 1142–1151 (2003).

14 Walsh TJ, Viviani MA, Arathoon E et al. New targets and delivery systems for antifungal therapy. Med. Mycol. 38(Suppl. 1), 335–347 (2000).

15 Groll AH, Piscitelli SC, Walsh TJ. Antifungal pharmacodynamics:

concentration-effect relationships in vitro and in vivo. Pharmacotherapy 21(8 Pt 2), 133S–148S (2001).

16 McCormack PL, Perry CM. Caspofungin:

a review of its use in the treatment of fungal infections. Drugs 45, 2049–2068

(2005).

Review

Somer, Törün & Salman

17 Zaoutis TE, Benjamin DK, Steinbach W. Antifungal treatment in pediatric patients. Drug Resist. Update 8, 235–245 (2005).

18 Garnock-Jones KP, Kearn SJ. Caspofungin in pediatric patients with fungal infections. Pediatr. Drugs 11, 259–269

(2009).

19 Louie A, Deziel M, Liu W et al. Pharmacodynamics of caspofungin in a murine model of systemic candidiasis:

importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob. Agents Chemother. 49, 5058–5068 (2005).

20 Pfaller MA, Boyken L, Hollis HJ et al. In vitro susceptibilities of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J. Clin. Microbiol. 46, 150–156 (2008).

21 VandenBussche HL, Van Loo DA. A clinical review of echinocandins in pediatric patients. Annal. Pharmacotherapy 44, 166–177 (2010).

22 Odio CM, Araya R, Pinto LE et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr. Infect. Dis. J. 23, 1093–1097 (2004).

23 Antachopoulos C, Meletiadis J, Sein T, Roilides E, Walsh TJ. Comparative in vitro pharmacodynamics of caspofungin, micafungin, and anidulafungin against germinated and nongerminated Aspergillus conidia. Antimicrob. Agents Chemother. 52, 321–328 (2008).

24 Bowman JC, Hicks PS, Kurtz MB et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob. Agents Chemother. 46, 3001–3012 (2002).

25 Wiederhold NP, Kontoyiannis DP, Chi J et al. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration- dependent activity. J. Infect. Dis. 190, 1464–1471 (2004).

26 Douglas CM. Understanding the microbiology of the Aspergillus cell wall and the efficacy of caspofungin. Med. Mycol. 44(Suppl.), 95–99 (2006).

27 Feldmesser M, Kress Y, Mednick A, Casadevall A. The effect of the echinocandin analogue caspofungin on cell wall glucan synthesis by Cryptococcus neoformans. J. Infect. Dis. 182, 1791–1795

(2000).

28 Almyroudis NG, Sutton DA, Fothergill AW, Rinaldi MG, Kusne S. In vitro susceptibilities of 217 clinical

isolates of zygomycetes to conventional and new antifungal agents. Antimicrob. Agents Chemother. 51, 2587–2590 (2007).

29 Zeng J, Kamei K, Zheng Y, Nishimura K. Susceptibility of Pseudallescheria boydii and Scedosporium apiospermum to new antifungal agents. Nippon Ishinkin Gakkai Zasshi 45, 101–104 (2004).

30 Groll AH, Walsh TJ. Antifungal agents. In: Feigin and Cherry’s Textbook of Pediatric Infectious Diseases (6th Edition). Feigin RD, Demmler-Harrison GJ, Cherry JD, Kaplan SL (Eds). Saunders, Elsevier, PA, USA, 3271–3308 (2009).

31 Shalit I, Shadkchan Y, Mircus G, Osherov N. In vitro synergy of caspofungin with licensed and novel antifungal drugs against clinical isolates of Fusarium spp. Med. Mycol. 47, 457–461 (2009).

32 Park S, Kelly R, Kahn JN et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida spp. Isolates. Antimicrob. Agents Chemother. 49, 3264–3273 (2005).

33 Hernandez S, Lopez-Ribot JL, Najvar LK et al. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob. Agents Chemother. 49, 767–769 (2005).

34 Chapeland-Leclerc F, Hennequin C, Papon N et al. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob. Agents Chemother. 54, 1360–1362 (2010).

35 Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-b- d -glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob. Agents Chemother. 53, 3690–3699 (2009).

36 Pfaller MA, Diekema DJ, Ostrosky-Zeichner L et al. Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J. Clin. Microbiol. 46, 2620–2629 (2008).

37 Gardiner RE, Souteropoulos P, Park S, Perlin DS. Characterization of Aspergillus fumigatus mutants with reduced susceptibility to caspofungin. Med. Mycol. 43(Suppl. 1), S299–S305 (2005).

38 Antachopoulos C, Meletiadis J, Sein T, Roilides E, Walsh TJ. Concentration- dependent effects of caspofungin on the metabolic activity of Aspergillus species. Antimicrob. Agents Chemother. 51, 881–887

(2007).

39 Ramage G, VandeWalle K, Bachmann SP, Wickes BL, Lopez-Ribot JL. In vitro pharmacodynamic properties of three antifungal agents against performed Candida albicans biofilms determined by time-kill studies. Antimicrob. Agents Chemother. 46, 3634–3636 (2002).

40 Stevens DA, White TC, Perlin DS et al. Studies of the paradoxical effect of caspofungin at high concentrations. Diagn. Microbiol. Infect. Dis. 51, 173–178 (2005).

41 Hadju R, Thompson R, Sundelof JG et al. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob. Agents Chemother. 41, 2339–2344 (1997).

42 Benjamin DK Jr, Stoll BJ, Fanaroff AA et al. Neonatal candidiasis among extremely low birthweight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 and 22 months. Pediatrics 117, 84–92 (2006).

43 Sáez-Llorens X, Macias M, Maiya P et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob. Agents Chemother. 53, 869–875 (2009).

44 Groll AH, Gullick BM, Petraitiene R et al. Compartmental pharmacokinetics of the antifungal echinocandin caspofungin (MK-0991) in rabbits. Antimicrob. Agents Chemother. 45, 596–600 (2001).

45 Stone JA, Holland SD, Wickersham PJ et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob. Agents Chemother. 46, 739–745 (2002).

46 Stone JA, Xu X, Winchell GA et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob. Agents Chemother. 48, 815–823 (2004).

47 Graybill JR. The echinocandins, first novel class of antifungals in two decades: will they live up to their promise? Int. J. Clin. Pract. 55, 633–638 (2001).

48 Walsh TJ, Adamson PC, Seibel NL et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob. Agents Chemother. 49, 4536–4545 (2005).

• Investigation of the pharmacokinetics of caspofungin in different pediatric age groups.

Caspofungin therapy in immunocompromised children & neonates

Review

49 Sanz-Rodriguez C, Lopez-Duarte M, Jurado M et al. Safety of the concomitant use of caspofungin and cyclosporine A in patients with invasive fungal infections. Bone Marrow Transplant. 34, 13–20

(2004).

50 Neely M, Jafri HS, Seibel N et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob. Agents Chemother. 53, 1450–1458 (2009).

51 Koo A, Sung L, Allen U et al. Efficacy and safety of caspofungin for the empiric management of fever in neutropenic children. Pediatr. Infect. Dis. J. 26, 854–856 (2007).

52 Groll AH, Walsh TJ. Caspofungin:

pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin. Invest. Drugs 10, 1545–1558 (2001).

53 Steinbach WJ, Benjamin DK. New antifungal agents under development in children. Curr. Opin. Infect. Dis. 18, 484–489 (2005).

54 Lehrnbecher T, Groll AH. Caspofungin in pediatric patients. Pediatric Health 2, 677–685 (2008).

55 Fisher BT, Zaoutis T. Caspofungin for treatment of pediatric fungal infections. Pediatr. Infect. Dis. J. 27, 1099–1101

(2008).

56 Groll AH, Attarbashi A, Schuster F et al. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J. Antimicrob. Chemother. 57, 527–535 (2006).

• Large retrospective analysis of safety and efficacy of caspofungin in 64 severely immunocompromised children.

57 Zaoutis T, Lehrnbecher T, Groll AH et al. Safety experience with caspofungin in pediatric patients. Pediatr. Infect. Dis. J. 28, 1132–1135 (2009).

58 Mycamine package insert. Astellas Pharma, Deerfield, IL, USA (2008).

59 Franklin JA, McCormick J, Flynn PM. Retrospective study of safety of caspofungin in immunocompromised pediatric patients. Pediatr. Infect. Dis. J. 22, 747–749 (2003).

60 Merlin E, Galambrun C, Ribaud P et al. Efficacy and safety of caspofungin therapy in children with invasive fungal infections. Pediatr. Infect. Dis. J. 25, 1186–1188

(2006).

61 Cesaro S, Giacchino M, Locatelli F et al. Safety and efficacy of a caspofungin-based combination therapy for treatment of

proven or probable aspergillosis in pediatric hematological patients. BMC Infect. Dis. 7, 28 (2007).

62 Mrowczynski W, Wojtalik M. Caspofungin for Candida endocarditis. Pediatr. Infect. Dis. J. 23, 376 (2004).

63 Wertz KK, Pretzlaff RK. Caspofungin in a pediatric patient with persistent candidemia. Pediatr. Crit. Care Med. 5, 181–183 (2004).

64 Castagnola E, Machetti M, Cappelli B et al. Caspofungin associated with amphotericin B or voriconazole for

treatment of refractory fungal pneumonia

in children with acute leukemia or

undergoing allogeneic bone marrow transplant. Clin. Microbiol. Infect. 10, 255–257 (2004).

65 Yalaz M, Akisu M, Hilmioglu S, Calkavur S, Cakmak B, Kultursay N. Successful caspofungin treatment of multidrug resistant Candida parapsilosis septicemia in an extremely low birth weight neonate. Mycoses 49, 242–245 (2006).

66 Madero L, Sanchez de Toledo J, Castel V,

Sevilla J, Gonzalez-Esteban J, Sanz-Rodriguez C. Compassionate use study of caspofungin

in children with proven or suspected invasive

mycosis or persistent febrile neutropenia.

J. Chemother. 21, 229–231 (2009).

67 Zaoutis TE, Jafri HS, Huang LM et al.

A prospective, multicenter study of

caspofungin for the treatment of documented Candida and Aspergillus infections in pediatric patients. Pediatrics

••

123, 877–884 (2009).

First prospective, multicenter study of caspofungin in pediatric patients with invasive fungal infections.

68 Maertens JA, Madero L, Reilly AF et al.

A randomized, double-blind, multicenter

trial of caspofungin versus liposomal amphotericin B for empirical antifungal

therapy of pediatric patients with persistent fever and neutropenia. Pediatr. Infect. Dis.

J. 29, 415–420 (2010).

••

Large and well designed clinical trial of 82 pediatric patients comparing efficacy and safety of caspofungin versus amphotericin B for empiric treatment of febrile neutropenia.

69 Prasad PA, Coffin SE, Leckerman KH, Walsh TJ, Zaoutis TE. Pediatric antifungal utilization: new drugs, new trends. Pediatr. Infect. Dis. J. 27, 1083–1088 (2008).

70 Hesseling M, Weindling M, Neal T. First reported use of caspofungin in an extremely low-birth-weight neonate. J. Matern. Fetal Neonatal Med. 14, 212 (2003).

71 Natarajan G, Lulic-Botica M, Rongkavilit C, Pappas A, Bedard M. Experience with caspofungin in the treatment of persistent fungemia in neonates. J. Perinatol. 25, 770–777 (2005).

72 Odio CM, Castro CE VS Jr, Lazo JJ, Herrera ML. Caspofungin (CAS) therapy (Tx) for neonates (Ns) with invasive candidiasis (IC) cared for at intensive care units (ICU) (Abstract G-976). Presented at: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA, 17–20 September 2007.

73 Smith PB, Steinbach WJ, Cotton CM et al. Caspofungin for the treatment of azole resistant candidemia in a premature infant. J. Perinatol. 27, 127–129 (2007).

74 Natale F, Castronovo A, Regoli D, De Curtis M, Manzoni P. Successful treatment with caspofungin of refractory Candida krusei candidemia in a very low birth weight preterm infant. Pediatr. Infect. Dis. J. 28, 452 (2009).

75 Elanjikal Z, Sorensen J, Schmidt H et al. Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis. Pediatr. Infect. Dis. J. 22, 653–656 (2003).

76 Vagace JM, Sanz-Rodriguez C, Casado M et al. Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report. BMC Infect. Dis 7, 40 (2007).

77 Haase R, Kreft B, Foell J, Kekulé AS, Merkel N. Successful treatment of Candida albicans septicemia in a preterm infant with severe congenital ichthyosis (Harlequin baby). Pediatr. Dermatol. 26, 575–578

(2009).

78 Ting JY, Chan S, Lung DS et al. Intra- abdominal Rhizopus microsporus infection successfully treated by combined aggressive surgical, antifungal, and iron chelating therapy. J. Pediatr. Hematol. Oncol. 32, e238–e240 (2010).

79 Cesaro S, Toffolutti T, Messina C et al. Safety and efficacy of caspofungin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycoses. Eur. J. Haematol. 73, 50–55 (2004).

80 Castagnola E, Francheschi A, Natalizia AR, Montero E, Tuo P. Combined antifungal therapy for persistent central venous catheter-related candidemia in extremely low birth weight neonates. J. Chemother. 21, 234–235 (2009).