Abstract
The safety profile of fluconazole was assessed for 562 children (ages, 0 to 17 years) comprising 323 males and 239 females. The data are derived from 12 clinical studies of fluconazole as prophylaxis or treatment for a variety of fungal infections in predominantly immunocompromised patients. Most children received multiple doses of fluconazole in the range of 1 to 12 mg/kg of body weight; a few received single doses. Administration was mainly by oral suspension or intravenous injection. Overall, 58 (10.3%) children reported 80 treatment-related side effects. The most common side effects were associated with the gastrointestinal tract (7.7%) or skin (1.2%). Self-limiting, treatment-related side effects affecting the liver and biliary system were reported in three patients (0.5%). Overall, 18 patients (3.2%) discontinued treatment due to side effects, mainly gastrointestinal symptoms. Dose and age did not appear to influence the incidence and pattern of side effects. Treatment-related laboratory abnormalities were uncommon, the most frequent being transient elevated alanine aminotransferase (4.9%), aspartate aminotransferase (2.7%), and alkaline phosphatase (2.3%) levels. Although 98.6% of patients were taking concomitant medications, no clinical or laboratory interactions were observed. The safety profile of fluconazole was compared with those of other antifungal agents, mostly oral polyenes, by using a subset of data from five controlled studies. Side effects were reported by more patients treated with fluconazole (45 of 382; 11.8%) than by those patients treated with comparable agents (25 of 381; 6.6%); vomiting and diarrhea were the most common events in both groups. The incidence and type of treatment-related laboratory abnormalities were similar for the two groups. In conclusion, fluconazole was well tolerated by the pediatric population, many of whom were suffering from severe underlying disease and were taking a variety of concurrent medications. The safety profile of fluconazole in children mirrors the excellent safety profile seen in adults.
Fluconazole, an orally active synthetic bis-triazole, is established worldwide as a leading antifungal agent (13). It has an important role in the treatment and prophylaxis of fungal infections in immunocompromised adults (12).
Fluconazole is well tolerated in adult patients, including those who are seriously ill (21). The safety profile of the drug has been defined by data from clinical trials involving more than 4,000 adult patients, of whom approximately one-third had AIDS (21a). All patients received fluconazole therapy for at least 7 days. Overall, 16% experienced treatment-related side effects, most commonly gastrointestinal effects (nausea, 3.7%; abdominal pain, 1.7%; vomiting, 1.7%; diarrhea, 1.5%), headache (1.9%), and skin rash (1.8%). Side effects did not appear to be correlated with dosage over a range of 50 to 400 mg daily. Few patients were withdrawn from the study due to treatment-related side effects or laboratory abnormalities (1.5 and 1.2%, respectively). Fluconazole had no consistent effect on patients’ biochemical parameters. Although isolated instances of clinically overt hepatic dysfunction have been reported in patients with AIDS, fluconazole appears to have less hepatotoxic potential than other azoles (10, 19). Data from a prescription-event monitoring study involving more than 15,000 adult patients have confirmed that fluconazole is well tolerated and is associated with very few side effects (15, 16).
Opportunistic fungal infections are also an important cause of morbidity and mortality in immunocompromised children (22, 27). Neutropenia induced by chemotherapy places the pediatric patient at risk of serious fungal infection, most commonly with Candida spp. (22). Mucosal candidiasis is the most frequent opportunistic infection affecting children with human immunodeficiency virus (HIV) infection (11).
Fluconazole has recently been approved for pediatric use and shows promise in the treatment and prophylaxis of fungal infections in immunocompromised children (4, 5, 9, 14, 18, 20, 26). This review summarizes pediatric safety data obtained during phase II and III clinical studies of fluconazole (1, 9, 14, 17, 20, 23, 24).
MATERIALS AND METHODS
Data were obtained from six pharmacokinetic studies and six therapeutic studies carried out in Europe, the United States, and Canada (1, 9, 14, 17, 20, 23, 24). A subset of these data from five controlled studies was used to compare the safety profile of fluconazole with those of other antifungal agents (9, 14, 20). Fluconazole was evaluated as prophylaxis or treatment for a variety of fungal infections, including oropharyngeal candidiasis, candidemia, and disseminated candidiasis. Many of the patients who were recruited were immunocompromised, primarily due to chemotherapy, radiotherapy, HIV infection, or transplantation. Ethics committee approval and written informed consent of the parents or legal guardians of the children were obtained. Study details are summarized in Tables 1 and 2.
TABLE 1.
Details of pharmacokinetic studiesa
| Study no. | No. of centers, location | Underlying diagnosis | Fluconazole dosage (mg/kg/day), route of administration | Duration or type of therapy | No. of patients | Mean age (range) | Reference |
|---|---|---|---|---|---|---|---|
| 006 | 2, USA | Cancer chemotherapy | 2, 4, or 8, i.v. | 7 days | 26 | 11.2 yr (5–15 yr) | Lee et al. (17) |
| 018 | 6, USA | Oncological malignancy, with patients receiving chemotherapy, radiation, or supportive care, or HIV infection | 2 or 8, p.o. | Single dose | 45 | 2 mg, 6.3 yr; 8 mg, 5.8 yr (9 mo–13 yr) | Brammer and Coates (1) |
| 239 | 1, UK | Malignant disease or BMT; expectation of neutropenia | 3, p.o.b | 1–41 days | 16 | 4.6 yr (0–10 yr) | Pfizer, Inc. (21a) |
| 241 | 1, France | Acquired or congenital immune deficiency syndromes | 3, i.v. | Single dose | 16 | 65.9 wk (1.6–293.1 wk) | Brammer and Coates |
| 247 | 1, UK | Malignant disease or BMT; expectation of neutropenia | 3, p.o.b | 4–20 days | 13 | 7.2 yr (1–12 yr) | Brammer and Coates (1) |
| 375 | 1, Finland | Prematurity, very low birth weight | 6 every 72 h, i.v. | 2–5 doses | 12 | 23.7 h (8.6–35.7 h) | Saxén et al. (24) |
Abbreviations: USA, United States; UK, United Kingdom; i.v., intravenously; p.o., orally; BMT = bone marrow transplantation.
Single dose followed 48 h later by daily dosing.
TABLE 2.
Details of therapeutic studiesa
| Study no. | No. of centers, location | Underlying diagnosis | Indication | Fluconazole dosage (mg/kg/day), route of administration | Comparator(s) |
|---|---|---|---|---|---|
| 178 | 32, USA | Immunocompromise | Oropharyngeal candidiasis | 2 or 3, p.o.b | Nystatin, 1,600,000 U, p.o. |
| 368 | 1, France | HIV infection | Prophylaxis | 1, p.o. | Ketoconazole, 5 mg/kg, p.o. |
| 369 | 1, UK | Prematurity | Prophylaxis | 1, p.o. or i.v. | Nystatin, 400,000 U, p.o. |
| 370 | 7, Europe | HIV infection | Oropharyngeal candidiasis | 2 or 3, p.o. | Ketoconazole, 3.5 or 7 mg/kg, p.o. |
| 372 | 12, Europe | None | Systemic fungal infection | 6–12, p.o. or i.v. | None |
| 373 | 23, Europe and Canada | Hematological or oncological malignancy | Prophylaxis | 3, p.o. | Nystatin, 50,000 U/kg, p.o. or amphotericin B, 25 mg/kg, p.o. |
| Mean duration of therapy [days (range)]
|
No. of patients
|
Mean age (range)
|
Reference | |||
|---|---|---|---|---|---|---|
| Fluconazole-treated group | Comparison group | Fluconazole-treated group | Comparison group | Fluconazole-treated group | Comparison group | |
| 13 (1–29) | 12 (2–27) | 94 | 88 | 5.1 yr (NA) | 5.3 yr (NA) | Flynn et al. (9) |
| 90 (53–129) | 68 (8–134) | 6 | 7 | 5.8 yr (1–12 yr) | 3.7 yr (0–7 yr) | Pfizer, Inc. (21a) |
| 13 (1–18) (p.o.) and 16 (14–19) (i.v.) | 18 (15–35) | 7 (p.o.) and 6 (i.v.) | 7 | 17.9 d (5–47 d) (p.o.) 21.2 d (9–38 d) (i.v.) | 9.9 d (6–20 d) | Pfizer, Inc. (21a) |
| 14 (6–33) | 16 (5–49) | 24 | 22 | 4.6 yr (0–14 yr) | 3.8 yr (0–12 yr) | Hernández-Sampelayo et al. (14) |
| 20 (5–162) | 51 | 5.3 yr (0.1–17 yr) | Presterl et al. (23) | |||
| 28 (1–89) | 29 (1–112) | 245 | 257 | 6.8 yr (0–17 yr) | 6.8 yr (0–17 yr) | Ninane et al. (20) |
Abbreviations: USA, United States; UK, United Kingdom; p.o., orally; i.v., intravenously; NA, not available; d, days.
Loading dose of 4 or 6 mg/kg on first day of treatment.
Side effects were recorded at each clinical assessment if they were reported spontaneously by the patient or a parent or guardian of the patient or if they were observed by the investigator. The relationship to treatment was assessed by the investigator. Laboratory data were collected at the baseline and were monitored throughout the study period. In the multiple-dose studies, laboratory tests were generally repeated at weekly intervals. Since many of the children were seriously ill, the underlying disorder and effects of concomitant therapy were taken into consideration in the assessment of the relationship of laboratory abnormalities to treatment.
Fluconazole was evaluated at dosages ranging from 1 to 12 mg/kg of body weight once daily (Table 3). The majority of children (66%) received 3 mg/kg (prophylactic dose), equivalent to an adult dose of 100 mg, while 33% received 6 to 12 mg/kg (treatment dose), equivalent to 200 to 400 mg in an adult. Most children (88%) were given multiple doses over several days; the remainder received a single dose. The mean duration of therapy at a dose of 3 mg/kg was 3 weeks. Fluconazole was administered predominantly as an oral suspension (81%) or an intravenous injection (18%).
TABLE 3.
Dosages and durations of treatment for total patient population treated with fluconazole
| Dosage (mg/kg/day) | No. of patientsa | Treatment duration (days)
|
|
|---|---|---|---|
| Mean | Range | ||
| 1 | 20 | 37 | 1–129 |
| 2 | 62 | 8 | 1–50 |
| 3 | 372 | 21 | 1–89 |
| 4 | 44 | 7 | 1–97 |
| 6 | 102 | 4 | 1–45 |
| 8 | 66 | 7 | 1–42 |
| 12 | 20 | 8 | 1–24 |
Some patients received fluconazole at more than one dosage.
RESULTS
Data for 562 children treated with fluconazole are presented. More male than female patients were recruited; their ages ranged from premature neonatal age to age 17 years (Table 4).
TABLE 4.
Total patient population treated with fluconazole
| Sex | No. (%) of patients of the following ages:
|
|||||
|---|---|---|---|---|---|---|
| Total | <6 mo | 6 mo–2 yr | 2–5 yr | 5–14 yr | ≥14 yr | |
| Male | 323 | 23 | 40 | 72 | 168 | 20 |
| Female | 239 | 19 | 38 | 61 | 105 | 16 |
| Total | 562 | 42 (7.5) | 78 (13.9) | 133 (23.7) | 273 (48.6) | 36 (6.4) |
Side effects.
Overall, 58 (10.3%) fluconazole-treated patients reported 80 treatment-related side effects (Table 5). The most common side effects were associated with the gastrointestinal tract (7.7% of children), with vomiting (24 patients), diarrhea (12 patients), abdominal pain (10 patients), and nausea (4 patients) being the most frequent symptoms. The only other system with a greater than 1.0% incidence of side effects was the skin (1.2% of children). Three patients had an unspecified rash, two had an erythematous rash, one had pruritus, and one had a maculopapular rash. Side effects involving the special senses comprised taste perversion (four patients) and deafness (one patient). One case of purpura was reported.
TABLE 5.
Nature and incidence of treatment-related side effects in children treated with fluconazole, by age group
| Organ system affected | No. (%) of patients with side effects | No. of side effects by age group
|
||||
|---|---|---|---|---|---|---|
| 6 mo–2 yr (n = 78) | 2–5 yr (n = 133) | 5–14 yr (n = 273) | ≥14 yr (n = 36) | Totala (n = 562) | ||
| Total | 58 (10.3) | 8 | 17 | 44 | 11 | 80 |
| Gastrointestinal | 43 (7.7) | 6 | 10 | 34 | 7 | 57 |
| Skin | 7 (1.2) | 1 | 2 | 2 | 2 | 7 |
| Special sensesb | 5 (0.9) | 0 | 0 | 3 | 2 | 5 |
| Liver and biliary | 3 (0.5) | 1 | 1 | 1 | 0 | 3 |
| Cardiovascular | 2 (0.4) | 0 | 0 | 2 | 0 | 2 |
| Central and peripheral nervous | 2 (0.4) | 0 | 1 | 1 | 0 | 2 |
| Respiratory | 1 (0.2) | 0 | 2 | 0 | 0 | 2 |
| Hemopoietic | 1 (0.2) | 0 | 1 | 0 | 0 | 1 |
| General | 1 (0.2) | 0 | 0 | 1 | 0 | 1 |
No side effects were reported in infants aged less than 6 months (n = 42).
Taste perversion (four patients) and deafness (one patient).
Three treatment-related side effects associated with the liver and biliary system were reported. All occurred in children with leukemia who received fluconazole at 3 mg/kg as prophylaxis during chemotherapy-induced neutropenia. The first patient, a 2-year-old boy, showed transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels during fluconazole therapy. The second patient, a 9-year-old girl, developed hepatomegaly with moderate but sustained increases in AST and ALT levels; the condition resolved during follow-up. Jaundice and a small increase in serum bilirubin levels in the third patient, a boy aged 2 1/2 years, returned to normal during continued treatment. In all three patients, chemotherapy was also implicated as a possible cause of hepatotoxicity.
A total of 59 deaths occurred either during treatment or within 11 days of the cessation of treatment with fluconazole. None of the deaths was attributable to fluconazole therapy.
Almost all (98.6%) of the patients who were treated with fluconazole also received concurrent additional therapy. These most frequently consisted of other antimicrobial agents, corticosteroids, chemotherapeutic agents, immunosuppressants, and agents to relieve nausea and vertigo. No clinical or laboratory evidence of drug interaction with fluconazole was evident in these trials.
Overall, 18 of 562 patients (3.2%) treated with fluconazole discontinued treatment due to side effects. Fourteen of these withdrawals were considered to be related to therapy.
Higher doses of fluconazole did not appear to be associated with a higher incidence of treatment-related side effects (Table 6). One case of vomiting was the only reported treatment-related side effect among 20 children who received fluconazole at 12 mg/kg.
TABLE 6.
Incidence of treatment-related vomiting and diarrhea in children treated with fluconazole, by dose group
| Dose (mg/kg) | No. (%) of patients
|
||
|---|---|---|---|
| Total | Vomiting | Diarrhea | |
| 2 | 62 | 3 (4.8) | 1 (1.6) |
| 3 | 372 | 16 (4.3) | 9 (2.4) |
| 4 | 44 | 0 | 1 (2.2) |
| 6 | 102 | 1 (0.9) | 0 |
| 8 | 66 | 3 (4.5) | 1 (1.5) |
| 12 | 20 | 1 (5.0) | 0 |
Analysis of side effect data by age group was performed for the following age categories: <6 months, 6 months to 2 years, 2 to 5 years, 5 to 14 years, and ≥14 years (Table 5). None of the 42 infants who were younger than 6 months old developed any side effects. For children who were older than 6 months, there were no apparent differences in the incidence or pattern of reported side effects with age.
Laboratory tests.
Laboratory assessments included a complete blood count and tests of hepatic and renal function. Although clinically significant laboratory abnormalities were common, the vast majority were considered to be related to underlying diseases, concomitant medications, or intercurrent illnesses. The number and percentage of patients with abnormal laboratory test results that were considered to be possibly related to fluconazole therapy are shown in Table 7. Fluconazole did not have a clinically significant or consistent effect on any of the laboratory parameters. The most frequently reported (i.e., ≥2%) treatment-related laboratory test abnormalities were elevated ALT (4.9%), AST (2.7%), and alkaline phosphatase (2.3%) levels. Liver function abnormalities were usually transient, with the test results generally returning to normal values during therapy or after completion of the study.
TABLE 7.
Nature and incidence of treatment-related laboratory abnormalities in children treated with fluconazole
| Parameter | No. of patients tested | No. (%) of patients with abnormalitiesa |
|---|---|---|
| Hematology | ||
| Hemoglobin concn | 547 | 4 (0.7) |
| Leukocyte count | 542 | 0 |
| Neutrophil count | 473 | 0 |
| Eosinophil count | 470 | 6 (1.3) |
| Platelet count | 539 | 5 (0.9) |
| Hepatic function | ||
| AST (SGOTb) level | 490 | 13 (2.7) |
| ALT (SGPTc) level | 472 | 23 (4.9) |
| Alkaline phosphatase level | 428 | 10 (2.3) |
| Total bilirubin concn | 405 | 5 (1.2) |
| Renal function | ||
| Blood urea nitrogen concn | 193 | 1 (0.5) |
| Urea concn | 13 | 0 |
| Creatinine concn | 525 | 0 |
Laboratory abnormalities were not necessarily reported as side effects.
SGOT, serum glutamic oxalacetic transaminase.
SGPT, serum glutamic pyruvic transaminase.
Two children (0.4%) discontinued fluconazole treatment because of laboratory parameter abnormalities; both patients had elevated levels of AST and ALT. One of these patients was a 9-year-old girl with lymphoblastic leukemia who received fluconazole at a dose of 2 mg/kg for 5 days. The other patient, a 10-year-old boy with a diagnosis of alveolar rhabdomyosarcoma, received a dose of 8 mg/kg for 6 days. In both patients, liver function test results were returning toward normal at the final assessment.
Comparative studies.
The safety profile of fluconazole was compared with those of other antifungal agents by using data from five controlled studies (9, 14, 20). Three hundred eighty-two children received fluconazole. Of the 381 patients in a comparable group, most were treated with the oral polyenes amphotericin B and nystatin (n = 352; 92.4%), and a few received ketoconazole (n = 29; 7.6%). The age distributions and dosing durations for the fluconazole-treated and the comparison groups were well matched. In both groups, the majority of patients were ages 5 to 14 years (fluconazole-treated group, 46.6%; comparison group, 48.0%) or 2 to 5 years (fluconazole-treated group, 28.3%; comparison group, 30.7%). About two-thirds of the patients received therapy for at least 7 days and less than 28 days (fluconazole-treated group, 65.7%; comparison group, 64.6%). The maximum durations of treatment were 129 days for the fluconazole-treated group and 134 days for the comparison group.
Side effects were reported by more patients who received fluconazole than by patients who received the other agents (11.8 versus 6.6%; Table 8). The types of side effects reported were similar to those who received fluconazole and those who received other drugs; vomiting and diarrhea were the most common symptoms in both groups. Withdrawal due to side effects was reported for 15 of 382 patients (3.9%) who received fluconazole, 4 of 352 patients (1.1%) who received oral polyenes, and 1 of 29 patients (3.4%) who received ketoconazole. Withdrawal was considered to be drug related in 12 patients who received fluconazole and 3 treated with oral polyenes.
TABLE 8.
Nature and incidence of treatment-related side effects in comparative studies
| Group or parameter | No. (%) of patients
|
|
|---|---|---|
| Fluconazoletreated group | Comparison group | |
| All patients assessed | 382 | 381 |
| Patients with side effects | 45 (11.8)a | 25 (6.6)a |
| Patients withdrawn because of side effects | 15 (3.9) | 5 (1.3) |
| Total side effects | 57 | 33 |
| Gastrointestinal system | ||
| Vomiting | 16 (4.2) | 12 (3.1) |
| Diarrhea | 11 (2.9) | 7 (1.8) |
| Abdominal pain | 9 (2.4) | 4 (1.0) |
| Other gastrointestinal | 10 | 5 |
| Skin | 5 | 0 |
| Liver and biliary | 3 | 0 |
| Respiratory | 2 | 2 |
| Central and peripheral nervous | 1 | 1 |
| Musculoskeletal | 0 | 2 |
Chi-square test value = 6.234 (P value < 0.02).
In general, the incidence of treatment-related laboratory abnormalities was similar in both groups (Table 9). Liver function abnormalities occurred at similar frequencies in groups treated with fluconazole and the oral polyenes. Although the incidence of elevated AST and ALT levels appeared to be higher (approximately double) for the ketoconazole-treated group than for the groups treated with fluconazole and the oral polyenes, the number of patients who received ketoconazole was small.
TABLE 9.
Nature and incidence of treatment-related laboratory abnormalities in comparative studies
| Parameter | Fluconazole
|
Oral polyenes
|
Ketoconazole
|
|||
|---|---|---|---|---|---|---|
| No. of patients tested | No. (%) of patients with abnormalitiesa | No. of patients tested | No. (%) of patients with abnormalitiesa | No. of patients tested | No. (%) of patients with abnormalitiesa | |
| Hematology | ||||||
| Hemoglobin concn | 373 | 2 (0.5) | 343 | 1 (0.3) | 23 | 0 |
| Leukocyte count | 375 | 0 | 344 | 0 | 25 | 1 (4.0) |
| Neutrophil count | 320 | 0 | 302 | 0 | 20 | 0 |
| Eosinophil count | 324 | 4 (1.2) | 308 | 2 (0.6) | 19 | 0 |
| Platelet count | 372 | 4 (1.1) | 342 | 0 | 24 | 0 |
| Hepatic function | ||||||
| AST (SGOTb) level | 333 | 8 (2.4) | 309 | 10 (3.2) | 20 | 1 (5.0) |
| ALT (SGPTc) level | 316 | 18 (5.7) | 289 | 17 (5.9) | 19 | 2 (10.5) |
| Alkaline phosphatase level | 291 | 8 (2.7) | 274 | 3 (1.1) | 14 | 0 |
| Total bilirubin concn | 284 | 3 (1.1) | 276 | 4 (1.4) | 13 | 0 |
| Renal function | ||||||
| Blood urea nitrogen concn | 88 | 0 | 83 | 0 | 0 | 0 |
| Creatinine concn | 357 | 0 | 324 | 0 | 15 | 0 |
Laboratory abnormalities were not necessarily reported as side effects.
SGOT, serum glutamic oxalacetic transaminase.
SGPT, serum glutamic pyruvic transaminase.
DISCUSSION
Fluconazole was well tolerated by the study population of 562 children, many of whom were suffering from severe underlying disease such as HIV infection or hematological or oncological malignancies. The predominant reported side effects were gastrointestinal symptoms. In patients undergoing treatment for cancer, side effects such as nausea and vomiting may have been associated with the administration of chemotherapy or radiotherapy. The incidence and pattern of side effects were similar in all age groups and did not appear to be related to dose over the range studied. Both the most common dose of 3 mg/kg (equivalent to 100 mg in a 70-kg adult) and the highest dose of 12 mg/kg (equivalent to 400 mg in a 70-kg adult) were well tolerated, albeit by a small number of patients treated with the higher dose. These data confirm the favorable tolerability and safety profile observed in other published studies of fluconazole used in children (4–8, 17, 18, 25, 26).
Dosage recommendations for fluconazole in pediatric patients have been established on the basis of pharmacokinetic studies involving more than 100 children (1). The volume of distribution and elimination rate in pediatric patients differed significantly from the values reported for adults (2, 3). The volume of distribution varied with age, being greatest in neonates and decreasing by young adulthood to a value approaching that for adults. With the exception of neonates, elimination was generally more rapid in children than in adults, with a mean plasma elimination half-life of about 20 h for all pediatric age groups. In neonates and premature babies, however, fluconazole was eliminated slowly, with a mean elimination half-life of 88.6 h at birth, decreasing to 55.2 h at age 2 weeks. Appropriate dosage recommendations for pediatric patients have been developed to ensure that the concentrations attained in the plasma of children are comparable to those seen in the plasma of adults receiving currently recommended dosages.
Although fluconazole is not metabolized extensively by the liver, hepatotoxicity is a potential concern, particularly in very young or premature infants with suboptimal liver function. The results reported here, however, provide no evidence of significant drug-induced hepatotoxicity. Only three children (0.5%) had side effects related to the liver, and in all patients the symptoms resolved during continued treatment or follow-up. Transient increases in liver enzyme levels were identified in fewer than 5% of patients.
The data obtained in studies with adult and pediatric populations are not strictly comparable due to differences in the protocols, patient populations, and dosage regimens. Nevertheless, these results suggest that the pattern and incidence of side effects and laboratory abnormalities seen in children treated with fluconazole are analogous to those seen in adults. There were no indications of any unexpected safety concerns specifically related to children.
In conclusion, fluconazole was well tolerated in the pediatric population examined in this study. Many of the children were suffering from severe underlying disease and were taking a variety of concomitant medications. The safety profile of fluconazole in children mirrors the excellent safety profile seen in adults.
ACKNOWLEDGMENTS
We thank the investigators and colleagues who participated in the conduct and analysis of these studies: in the United States, M. Amantea, J. W. Lee, P. A. Pizzo, T. J. Walsh, and P. Whitcomb (Bethesda, Md.); D. Baker and P. M. Flynn (Memphis, Tenn.); G. Borowski, J. Malloy, and B. Norton (Montgomery, Ala.); Y. Bryson and A. Kovacs (Los Angeles, Calif.); N. Bunin (Philadelphia, Pa.); F. E. Cox (Augusta, Ga.); J. Cullen and B. Greffe (Denver, Colo.); C. K. Cunningham and L. Weiner (Syracuse, N.Y.); G. V. Dahl (Palo Alto, Calif.); A. Dajani (Detroit, Mich.); E. Farrington (Indianapolis, Ind.); G. Gilbert, B. Kramer, K. Lown, G. Noel, V. B. Peters, A. Rubinstein, and R. Warford (New York, N.Y.); M. Gooch (Salt Lake City, Utah); J. Harris, S. Pelton, and L. C. Wolfe (Boston, Mass.); M. Holdsworth (Albuquerque, N.M.); T. Kerkering (Richmond, Va.); J. Lukens (Nashville, Tenn.); H. Maurer, R. Yogev (Chicago, Ill.); M. Nahata (Columbus, Ohio); B. Parks (Jackson, Miss.); S. Paryani and P. A. Pitel (Jacksonville, Fla.); A. Petru (Oakland, Calif.); K. Powell, C. Schwartz (Rochester, N.Y.); M. Reed (Charlottesville, Va.); Z. Rodriguez, A. R. San Jorge, and G. Scott (Miami, Fla.); V. San Joaquin (Oklahoma City, Okla.); N. L. Seibel (Washington, D.C.); B. Sullivan (Marshfield, Mass.); R. Van Dyke and L. Yu (New Orleans, La.); E. Wald (Pittsburgh, Pa.); T. Yamauchi (Little Rock, Ark.); and G. Yee (Gainesville, Fla.); in Canada, D. Moore and L. de Repentigny (Montreal, Quebec); in Europe, L. M. Ball (Liverpool, United Kingdom); M. Bernacer Borja, T. Contra, T. Hernández-Sampelayo, M. I. de Jose, J. Lopez Perez, and B. Perez-Gorricho (Madrid, Spain); F. Berthold and A. Heinemann (Cologne, Germany); S. Blanche, E. Gluckman, C. Griscelli, and G. Leverger (Paris, France); F. Cockburn, B. S. Gibson, M. Greig, and T. Turner (Glasgow, United Kingdom); J. Cubells, C. Fortuny-Guasch, A. Mur-Sierra, and J. Sánchez de Toledo (Barcelona, Spain); P. J. Darbyshire (Birmingham, United Kingdom); R. Dopfer (Tübingen, Germany); H. Gadner and W. Graninger (Vienna, Austria); D. M. Gibb and I. M. Hann (London, United Kingdom); J. B. Gouvon (Dijon, France); A. Groll (Frankfurt, Germany); K. Hoppu, M. Pohjavuori, and H. Saxén (Helsinki, Finland); J. M. Indiano Arce (Bilbao, Spain); J. Kohler and A. Pallett (Southampton, United Kingdom); G. Margueritte (Montpellier, France); S. Meller (Sutton, United Kingdom); A. Navajas Guitierrez (Baracaldo, Spain); J. Ninane and E. Sariban (Brussels, Belgium); G. Paolucci (Bologna, Italy); N. Principi (Milan, Italy); P. Reinert (Creteil, France); A. Robert (Toulouse, France); H. J. Schmitt (Mainz, Germany); L. Sierra-Seumaga (Pamplona, Spain); R. F. Stevens (Manchester, United Kingdom); J. P. Vannier (Rouen, France); and C. Viscoli (Genova, Italy).
Footnotes
Corresponding author. Mailing address: Infectious Diseases Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond St., London WC1N 3JH, United Kingdom. Phone: (44) 171 405 9200. Fax: (44) 171 813 8266. E-mail: vnovelli@compuserve.com.
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