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Journal of Blood Medicine logoLink to Journal of Blood Medicine
. 2013 Feb 1;4:1–9. doi: 10.2147/JBM.S33906

Randomized double blind trial of ciprofloxacin prophylaxis during induction treatment in childhood acute lymphoblastic leukemia in the WK-ALL protocol in Indonesia

Pudjo H Widjajanto 1,, Sumadiono Sumadiono 1, Jacqueline Cloos 2,3, Ignatius Purwanto 1, Sutaryo Sutaryo 1, Anjo JP Veerman 1,2
PMCID: PMC3565570  PMID: 23403504

Abstract

Objectives

Toxic death is a big problem in the treatment of childhood acute lymphoblastic leukemia (ALL), especially in low-income countries. Studies of ciprofloxacin as single agent prophylaxis vary widely in success rate. We conducted a double-blind, randomized study to test the effects of ciprofloxacin monotherapy as prophylaxis for sepsis and death in induction treatment of the Indonesian childhood ALL protocol.

Methods

Patients were randomized to the ciprofloxacin arm (n = 58) and to the placebo arm (n = 52). Oral ciprofloxacin monotherapy or oral placebo was administered twice a day. All events during induction were recorded: toxic death, abandonment, resistant disease, and complete remission rate.

Results

Of 110 patients enrolled in this study, 79 (71.8%) achieved CR. In comparison to the placebo arm, the ciprofloxacin arm had lower nadir of absolute neutrophil count during induction with median of 62 (range: 5–884) versus 270 (range: 14–25,480) × 109 cells/L (P < 0.01), greater risks for experiencing fever (50.0% versus 32.7%, P = 0.07), clinical sepsis (50.0% versus 38.5%, P = 0.22), and death (18.9% versus 5.8%, P = 0.05).

Conclusion

In our setting, a reduced intensity protocol in a low-income situation, the data warn against using ciprofloxacin prophylaxis during induction treatment. A lower nadir of neutrophil count and higher mortality were found in the ciprofloxacin group.

Keywords: ciprofloxacin, prophylaxis, childhood acute lymphoblastic leukemia, randomized trial, low-income country

Introduction

Childhood acute lymphoblastic leukemia (ALL) patients may experience immunosuppression, either due to the disease or as a result of chemotherapy, or both. This condition occurs particularly during induction and re-induction phases, in which intensive treatment is conducted.13 It may lead to fatal infections, especially if the patients are malnourished and if there is lack of access to supportive care. Previous studies have shown that prophylactic antimicrobial treatment can reduce infection-related morbidity and mortality after oral or intravenous administration.49

Contrary to the setting in high-income countries, poverty, malnutrition, and the generally poor clinical condition of patients, as well as poor access to supportive care in low- to middle-income countries, have generated a higher incidence of treatment-related mortality and lower remission rates. A study in Dr Sardjito Hospital, Yogyakarta, Indonesia, as reported by Mostert et al,10 revealed that between 1997 and 2002 the toxic death rate was an obvious problem; approximately 23% of patients experienced treatment-related death and 35% refused or abandoned treatment. The majority of these events occurred during induction. Both events result in low remission and cure rates in our hospital setting.

We therefore conducted this randomized, double-blind study to test the role of ciprofloxacin oral monotherapy as prophylaxis for bacterial infection and toxic death during induction treatment of Indonesian childhood ALL protocol.

Patients and methods

Patients

The study groups consisted of children with ALL hospitalized in Dr Sardjito Hospital, Yogyakarta, Indonesia from July 1999 until June 2005, who met the inclusion criteria as follows: diagnosis of ALL based on French–American–British morphology classification of L1 or L2;11 and age between 0 and 14 completed years during induction treatment for the standard risk (SR) and high risk (HR) groups of the Indonesian Wijaya Kusuma (WK)-ALL-2000 protocol. Patients were defined as SR when their age at diagnosis was between 1 year and 9 completed years; their WBC count was less than 50 × 109/L; and there was an absence of mediastinal mass and no signs of central nervous system (CNS) involvement. Patients who did not meet SR criteria were assigned as HR. SR patients with a day 8 absolute peripheral lymphoblasts count 1 × 109/L or higher were upgraded to the HR group and treated accordingly. Fever was defined as an axillary temperature ≥ 38.5°C in a single determination or >38°C after two measurements with a 1-hour interval between each measurement. Clinical sepsis was defined when there was fever plus documented clinical signs and symptoms of systemic infection with or without increasing C-reactive protein level. Microbiological studies and surveillance were not always done for financial reasons.

The exclusion criteria were known allergy to quinolones, epilepsy, and/or body weight (BW) less than 10 kg. Patients were classified as undernourished at diagnosis when Z-score value was -2 SD or less based on weight-for-age (0–5 years) and height-for-age (5–15 years) World Health Organization standards for nutritional status.12,13

The WK-ALL-2000 protocol

The WK-ALL-2000 protocol for childhood ALL was developed in 1998–1999 as a relatively economical, reduced-intensity protocol to meet conditions in Indonesia after the Asian economical crisis.14 The protocol includes a 6-week induction treatment of three doses of weekly age-adjusted intrathecal methotrexate administered in weeks 0, 2, and 6; daily oral dexamethasone 6 mg/m2 for 42 days; five doses of weekly intravenous vincristine 1.5 mg/m2 during weeks 1–5; and two doses of intravenous Escherichia coli L-asparaginase 6000 IU/m2 in weeks 1 and 2 for SR or weeks 4 and 5 for HR patients. One dose of intravenous daunorubicin 30 mg/m2 was added at week 1 for HR patients only. HR patients also received a re-induction schedule inserted between the consolidation and maintenance phase. The scheme of the protocol is shown in Table 1.

Table 1.

Induction treatment of WK-ALL-2000 protocol.14

Medicine Schedule of administration
Methotrexate, ith Days 1, 15, 42
Dexamethasone 6 mg/m2, po Days 1–42
Vincristine 1.5 mg/m2, iv Days 8, 15, 22, 29, 36
L-asparaginase 6.000 U/m2, iv Days 8, 15 (standard-risk patients) or Days 29, 36 (high-risk patients)
Daunorubicin 30 mg/m2, iv Day 8 (high-risk patients only)

Notes: The dose of ith methotrexate was adjusted to age: <1 year = 6 mg; 1–2 years = 8 mg; 2–3 years = 10 mg; ≥ 3 years = 12 mg. The dose of oral dexamethasone was tapered-on during the first week when the initial WBC count was >20 × 109/L and tapered-off during the sixth week in all patients. Bone marrow aspirations were done on day 0 for diagnosis and at the end of induction treatment to determine remission achievement.

Abbreviations: ith, intrathecal; po, per oral; iv, intravenous; WK-ALL-2000, Wijaya Kusuma acute lymphoblastic leukemia protocol.

Random assignment

Patients were randomized using a computer into arm A and arm B. Arm A had tablets containing ciprofloxacin prepared in the pharmacy, while the placebo tablet contained tasteless material. Both the patients and the doctors and other staff were blinded to the tablet contents, and the groups were not unblinded until after the inclusion period had ended.

The tablets were taken orally twice per day from the onset of chemotherapy administration. The ciprofloxacin doses depended on the patient’s BW: BW 10–14 kg = 2 × 125 mg; BW 15–24 kg = 2 × 250 mg; BW 25–39 kg = 2 × 500 mg; and BW 40 kg or more = 2 × 750 mg. The tablets were taken continuously at home when the patient was discharged from hospital until completion of induction treatment. Modification of this treatment was permitted if the patient had fever.

Statistical analysis

The data were collected in a research-patient file and transferred to a computer spreadsheet form containing information of the protocol used, presentation at diagnosis (sex, age group, WBC group, risk group, nutritional status), day 8 peripheral lymphoblasts count, any fever and clinical sepsis, date of death or abandonment, and remission status at the end of the induction treatment.

The protocol stated day 43 as the end of induction treatment and remission determination. Patients achieved complete remission when their lymphoblast count in bone marrow was less than 5% without any signs of leukemic infiltration in peripheral blood, cerebrospinal fluid, or other organs. Abandonment of treatment, death, and no remission achievement were classified as induction failures.

The outcomes measured in this study were fever, clinical sepsis and mortality. The analysis was carried out using SPSS software (v13; IBM Corporation, Armonk, NY) and statistical significance was defined at the two-sided P-value < 0.05.

Results

One-hundred and ten patients were enrolled in this study and randomized into arm A (58 patients or 53%) and arm B (52 patients or 47%). The characteristics of patients were not equally divided between the two groups as shown in Table 2. The ciprofloxacin group was less often under-nourished than the placebo group (24.1% vs 44.2%, P = 0.03).

Table 2.

Characteristics of patients

Characteristics Placebo Ciprofloxacin Total P-value



n % n % n %
Total patients 52 47.3 58 52.7 110 100
Sex
 Male 34 65.4 37 60.3 69 62.7 0.86
 Female 18 34.6 21 39.7 41 37.3
Age group (years)
 1–9 40 76.9 49 84.5 89 80.9 0.31
 10–14 12 23.1 9 15.5 21 19.1
WBC at diagnosis (×109/L)
 <50 37 71.2 43 74.1 80 72.7 0.73
 ≥50 15 28.8 15 25.9 30 27.3
Risk group
 Standard risk 27 51.9 32 55.2 59 53.6 0.73
 High risk 25 48.1 26 44.8 51 46.4
Nutritional status
 Well-nourished 29 55.8 44 75.9 73 66.4 0.03
 Undernourished 23 44.2 14 24.1 37 33.6
Day 8 absolute peripheral lymphoblasts count (×109/L)a
 <1 40 80.0 44 80.0 84 80.0 1.00
 ≥1 10 20.0 11 20.0 21 20.0

Note:

a

Data were not available in five patients due to death or abandonment of treatment before measurement (n = 3 in ciprofloxacin group, n = 2 in placebo group).

Abbreviation: WBC, white blood cell.

Of the 110 patients, 79 (71.8%) achieved complete remission. Adverse outcomes during induction treatment were dominated by death (12.8%) and abandonment (9.0%). The remaining patients (6.4%) had resistant disease. Patients in the ciprofloxacin arm have a greater induction failure rate (31.0% vs 25.0%; 95% CI: 0.58–3.12; P = 0.48; Table 3), more fever (50.0% vs 32.7%; 95% CI: 0.95–4.47; P = 0.07), more clinical sepsis (50.0% vs 38.5%; 95% CI: 0.75–3.42; P = 0.22), and more toxic death (18.9% vs 5.8%; 95% CI: 0.92–13.80; P = 0.05). However, these results were not statistically significant. Twelve of 14 induction deaths occurred in the hospital; six of these were infective death, due to sepsis (five patients) and varicella (one patient) as shown in Table 4. However, the patients diagnosed with disseminated intravascular coagulation, multiorgan dysfunction syndrome, and shock may well have had infection as the causative event. The nadir of the absolute neutrophil count during induction in the ciprofloxacin arm was lower than in the placebo arm (median 62 [range: 5–884] vs 270 [range: 14–25,480] cells/μl; P < 0.01). The ciprofloxacin arm and the placebo arm had an equal induction duration (median 43 [range: 40–58] vs 43 [range: 39–59] days, respectively).

Table 3.

Outcomes during induction treatment

Outcomes Placebo Ciprofloxacin Total OR 95% CI P-value



n % n % n %
Total patients 52 47.3 58 52.7 110 100
Induction outcome
 Complete remission 39 75.0 40 69.0 79 71.8
 Induction failures 13 25.0 18 31.0 31 28.2 1.35a 0.58–3.12 0.48#
  Death 3 5.8 11 18.9 14 12.8 3.57a 0.92–13.80 0.05#
  Abandonment 7 13.5 3 5.2 10 9.0 0.42a 0.10–1.73 0.32##
  Resistant disease 3 5.8 4 6.9 7 6.4 1.3a 0.27–6.19 1.00##
Fever > 38.5°C
 Never 35 67.3 29 50.0 64 58.2
 Ever 17 32.7 29 50.0 46 41.8 2.06b 0.95–4.47 0.07#
Clinical sepsis
 Never 32 61.5 29 50.0 61 55.5
 Ever 20 38.5 29 50.0 49 44.5 1.60b 0.75–3.42 0.22#

Notes:

a

ORs for any induction failure and specific induction failures (CR is taken as the reference outcome category);

b

ORs for event of fever and clinical sepsis (Never is taken as the reference outcome category);

#

Chi-square test;

##

Fisher’s exact test.

Abbreviations: OR, odds ratio (ciprofloxacin group relative to placebo group); CI, confidence interval.

Table 4.

Cause of death during induction treatment

Causes of death Placebo Ciprofloxacin Total



n % n % n %
Total patients 3 11.4 11 78.6 14 100
Sepsis 3 5.8 2 3.4 5 35.7
Varicella 0 0 1 1.7 1 7.1
Intracranial hemorrhage 0 0 2 3.4 2 14.2
DIC 0 0 1 1.7 1 7.1
MODS 0 0 1 1.7 1 7.1
Hypovolemic shock 0 0 1 1.7 1 7.1
Transfusion reaction 0 0 1 1.7 1 7.1
No data or died at home 0 0 2 3.4 2 14.2

Abbreviations: DIC, disseminated intravascular coagulation; MODS, multiple organ dysfunction syndrome.

Table 5 shows that there was no significant difference in the incidence of diarrhea, nausea, vomiting, and neuritis as adverse events during induction between the ciprofloxacin arm and placebo arm. The characteristics and clinical outcome during induction treatment of each patient is shown in Table 6.

Table 5.

Adverse events during induction treatment

Events Placebo Ciprofloxacin Total



n % n % n %
Total patients 52 47.3 58 52.7 110 100
Nausea 8 15.4 3 5.2 11 10.0
Vomiting 7 13.5 6 10.3 13 11.8
Diarrhea 2 3.8 4 6.9 6 5.5
Neuritis 7 13.5 5 8.6 12 11.0

Table 6.

Presentation at diagnosis and clinical outcome

Patient Random Sex Age (years, months) WBC count (/μl) Risk group Nutritional state Day 8 response (/μl) Induction outcome Cause of death Fever Sepsis
1 Cip M 7, 02 <50,000 SR Well <1000 CR Ever Never
2 Pcb F 5, 05 ≥50,000 HR Well <1000 CR Never Never
3 Pcb F 5, 01 <50,000 SR Well ≥1000 CR Never Never
4 Cip F 3, 04 <50,000 SR Well <1000 CR Ever Ever
5 Cip M 10, 00 ≥50,000 HR Well <1000 CR Never Never
6 Cip F 10, 00 ≥50,000 HR Under <1000 RD Ever Never
7 Pcb M 1, 00 ≥50,000 HR Under ≥1000 CR Ever Ever
8 Cip M 4, 01 ≥50,000 HR Well ≥1000 Death Disseminated intravascular coagulation Ever Never
9 Pcb M 14, 01 ≥50,000 HR Under ≥1000 Death Sepsis Ever Ever
10 Cip M 4, 04 ≥50,000 HR Well <1000 Death Sepsis Ever Ever
11 Pcb M 7, 03 ≥50,000 HR Under <1000 Death Sepsis Never Never
12 Cip F 5, 11 ≥50,000 HR Well ≥1000 CR Ever Ever
13 Cip M 2, 07 <50,000 SR Under <1000 CR Ever Ever
14 Cip F 14, 01 ≥50,000 HR Well ≥1000 CR Ever Never
15 Cip M 8, 06 <50,000 SR Under <1000 CR Ever Ever
16 Cip F 1, 08 <50,000 SR Well <1000 CR Never Ever
17 Pcb M 2, 06 <50,000 SR Well <1000 CR Ever Ever
18 Pcb M 13, 00 <50,000 HR Under <1000 CR Never Ever
19 Cip M 1, 10 <50,000 HR Well <1000 CR Never Ever
20 Pcb M 2, 05 ≥50,000 HR Well <1000 CR Never Never
21 Pcb M 13, 01 <50,000 HR Well <1000 CR Never Never
22 Pcb F 9, 09 <50,000 SR Well <1000 CR Ever Never
23 Pcb F 6, 06 <50,000 SR Well <1000 CR Ever Ever
24 Cip F 6, 07 <50,000 SR Under <1000 CR Never Never
25 Cip M 2, 09 <50,000 SR Well <1000 CR Never Never
26 Pcb M 8, 01 <50,000 SR Well <1000 CR Never Never
27 Cip M 7, 05 <50,000 SR Well <1000 CR Never Ever
28 Cip M 1, 08 ≥50,000 HR Well <1000 CR Ever Ever
29 Pcb M 6, 03 <50,000 SR Under <1000 CR Never Never
30 Cip M 13, 00 ≥50,000 HR Well ≥1000 RD Ever Ever
31 Pcb M 2, 01 <50,000 SR Under <1000 CR Ever Ever
32 Pcb F 14, 00 ≥50,000 HR Under ≥1000 RD Never Never
33 Cip F 1, 06 <50,000 SR Well <1000 CR Never Ever
34 Pcb M 6, 06 <50,000 SR Well <1000 CR Never Ever
35 Cip M 3, 03 <50,000 SR Under <1000 CR Ever Ever
36 Pcb F 7, 08 <50,000 SR Well <1000 CR Never Never
37 Pcb M 3, 03 <50,000 SR Under <1000 Abn Never Ever
38 Pcb F 2, 11 <50,000 SR Well <1000 CR Never Never
39 Cip M 5, 01 <50,000 SR Well <1000 CR Ever Never
40 Cip M 3, 02 ≥50,000 HR Well <1000 CR Ever Never
41 Pcb M 4, 03 <50,000 SR Well <1000 CR Ever Ever
42 Pcb M 6, 07 <50,000 SR Well <1000 CR Never Never
43 Cip F 4, 00 <50,000 SR Under <1000 CR Ever Ever
44 Cip M 14, 00 ≥50,000 HR Under ≥1000 Abn Never Ever
45 Pcb M 4, 01 <50,000 SR Well <1000 CR Never Never
46 Pcb M 1, 03 <50,000 SR Well <1000 Abn Ever Ever
47 Pcb F 7, 07 <50,000 SR Well <1000 Abn Never Never
48 Pcb M 12, 01 <50,000 HR Under No data Abn Never Never
49 Pcb M 4, 02 <50,000 SR Under <1000 CR Ever Ever
50 Cip F 6, 05 <50,000 HR Well <1000 CR Ever Ever
51 Cip M 3, 04 <50,000 HR Well <1000 CR Never Never
52 Cip F 11, 00 <50,000 HR Under <1000 Death Sepsis Ever Ever
53 Pcb M 4, 08 ≥50,000 HR Well No data Death Sepsis Ever Ever
54 Cip M 2, 05 <50,000 HR Under No data Death Multiple organs dysfunction Ever Ever
55 Pcb M 5, 02 <50,000 SR Under <1000 CR Ever Never
56 Cip F 8, 01 <50,000 SR Well <1000 CR Never Never
57 Cip M 2, 08 <50,000 SR Well <1000 CR Ever Never
58 Cip M 4, 09 <50,000 HR Well <1000 CR Ever Ever
59 Cip M 9, 03 <50,000 SR Under <1000 RD Ever Never
60 Cip F 9, 07 <50,000 SR Well <1000 Death Hypovolemic shock Ever Ever
61 Cip M 2, 09 <50,000 SR Well No data Death Intracranial hemorrhage Ever Ever
62 Pcb F 5, 03 <50,000 SR Well <1000 CR Never Never
63 Pcb F 5, 07 ≥50,000 HR Under <1000 CR Never Ever
64 Cip M 3, 04 <50,000 SR Well ≥1000 CR Never Never
65 Cip M 8, 09 <50,000 SR Well <1000 CR Never Ever
66 Cip F 4, 08 <50,000 SR Under <1000 CR Never Never
67 Pcb F 2, 09 <50,000 SR Well <1000 RD Ever Ever
68 Cip F 2, 07 <50,000 SR Well ≥1000 Death No data Never Ever
69 Pcb F 6, 09 <50,000 SR Under ≥1000 CR Never Never
70 Cip M 10, 00 ≥50,000 HR Well <1000 CR Never Never
71 Pcb M 8, 01 ≥50,000 HR Under ≥1000 Abn Ever Ever
72 Cip M 3, 08 <50,000 SR Well ≥1000 CR Ever Ever
73 Cip M 5, 09 <50,000 HR Under <1000 CR Never Ever
74 Cip M 4, 01 <50,000 SR Well No data Abn Never Never
75 Cip F 13, 00 <50,000 HR Well ≥1000 Death No data Never Never
76 Cip M 2, 03 ≥50,000 HR Well ≥1000 RD Ever Ever
77 Pcb M 12, 01 <50,000 HR Well <1000 CR Never Never
78 Pcb M 8, 07 <50,000 SR Under <1000 CR Never Never
79 Cip F 4, 05 <50,000 SR Well <1000 CR Ever Never
80 Pcb M 2, 01 ≥50,000 HR Well ≥1000 CR Never Never
81 Pcb M 7, 05 ≥50,000 HR Under ≥1000 Abn Never Ever
82 Pcb M 11, 01 <50,000 HR Under <1000 CR Never Never
83 Pcb M 14, 00 ≥50,000 HR Well ≥1000 CR Never Never
84 Cip M 10, 00 <50,000 HR Well <1000 Death Varicella Never Never
85 Cip M 3, 08 <50,000 HR Well <1000 CR Never Never
86 Pcb M 12, 00 <50,000 HR Under <1000 CR Ever Ever
87 Cip F 2, 00 <50,000 SR Well <1000 CR Never Never
88 Cip M 5, 09 ≥50,000 HR Well <1000 Death Transfusion reaction Never Never
89 Cip M 4, 04 <50,000 SR Well <1000 CR Never Never
90 Pcb M 14, 01 ≥50,000 HR Under <1000 CR Ever Never
91 Pcb M 5, 05 <50,000 SR Well <1000 CR Never Never
92 Pcb M 2, 00 <50,000 SR Well <1000 RD Never Never
93 Cip M 3, 00 <50,000 SR Well <1000 CR Ever Ever
94 Pcb F 5, 04 <50,000 SR Under <1000 Abn Never Never
95 Cip M 3, 03 <50,000 SR Well <1000 CR Never Never
96 Pcb F 2, 02 <50,000 SR Well <1000 CR Never Never
97 Pcb M 1, 01 <50,000 HR Well <1000 CR Never Never
98 Pcb F 8, 02 ≥50,000 HR Under <1000 CR Never Ever
99 Cip F 6, 05 ≥50,000 HR Well <1000 Abn Never Never
100 Cip M 4, 09 ≥50,000 HR Well <1000 Death Intracranial hemorrhage Never Ever
101 Pcb F 4, 00 ≥50,000 HR Under <1000 CR Never Ever
102 Pcb F 3, 06 <50,000 SR Well <1000 CR Ever Ever
103 Cip M 3, 01 <50,000 HR Under ≥1000 CR Never Never
104 Pcb F 14, 00 <50,000 HR Well <1000 CR Ever Never
105 Cip M 3, 11 <50,000 SR Well <1000 CR Never Ever
106 Pcb M 8, 04 <50,000 HR Well ≥1000 CR Never Never
107 Pcb M 12, 01 <50,000 HR Under <1000 CR Never Never
108 Cip M 3, 06 <50,000 SR Under <1000 CR Ever Never
109 Cip F 5, 06 <50,000 SR Well <1000 CR Never Never
110 Cip F 5, 03 <50,000 SR Well <1000 CR Ever Ever

Abbreviations: Cip, ciprofloxacin; Pcb, placebo; F, female; M, male; SR, standard risk; HR, high risk; Well, well-nourished; Under, undernourished; CR, complete remission; RD, resistant disease; Abn, abandonment to treatment.

Discussion

Deaths, whether related to the disease itself or chemotherapy-induced, are common in leukemia treatment. The toxic death rate (23%) together with treatment refusal or abandonment of treatment (35%) are big problems in Dr Sardjito Hospital.10 These kinds of problems are typically found in resource-poor countries with poor and malnourished patients, poor access to supportive care, and lack of access to medicines.1517 The condition is contrary to that in high-income countries where toxic death rates are generally much fewer (2%–4%) and abandonment is virtually unknown.18,19 An important underlying cause of a high toxic death rate in childhood ALL is neutropenia, which may be found at diagnosis as a consequence of the leukemia itself, or following chemotherapy. Infections in individuals with neutropenia can develop into a life threatening condition and therefore require prompt intervention. Initiation of empiric antibiotics immediately after the neutropenic cancer patient becomes febrile has been the single most important advance in the management efforts to diminish mortality rates in the immunocompromized host.20 Unfortunately, trials to decrease the infection-related mortality in neutropenic patients utilizing antibacterial prophylaxis and the use of hematopoietic growth-stimulating factors have shown conflicting results.8,2124 In terms of primary antibiotic prophylaxis, ciprofloxacin or quinolone derivates have been widely used because they show wide antibacterial spectrum activity, mainly against Gram-negative bacteria from the gut, where invasive bacteria for systemic infection originate. Another benefit of quinolones, besides their effectiveness, is that they are generally well-tolerated and can be administered orally.7,25,26 Based on such findings, and because it is available at low-cost in our setting, we used ciprofloxacin in our study. We hypothesized that prophylactic ciprofloxacin administration would diminish infection and mortality during induction, thus increasing the remission and cure rates of childhood ALL in our hospital setting.

Some unexpected results were obtained in our study. First of all, the randomization was not balanced for malnutrition, and the ciprofloxacin group had the lower percentage of malnourished patients. It is clear that malnutrition is an important factor for fever and infection; nevertheless, patients in the ciprofloxacin arm showed a higher risk of developing fever, clinical sepsis, and death from complications than patients in the placebo arm. Therefore, we checked whether the groups had not been accidentally exchanged, but this was not the case: the arm A tablets indeed contained ciprofloxacin, and those of arm B were placebo. The finding of more toxic death in the ciprofloxacin arm in our study was contrary to most previous studies, which have shown reduced events of fever, sepsis, or mortality.6,9,27,28 We did not ascertain a definite cause for this finding.

Side effects related to ciprofloxacin in our study were mild and manageable, limited to nausea or vomiting and diarrhea as reported in previous studies.29,30 Neutropenia or marrow suppression caused by ciprofloxacin is rare.25 When we checked our database, however, we found that the ciprofloxacin group had a lower nadir of absolute neutrophil count. This may explain the higher incidence of fever, sepsis and death. It may moreover influence the gut flora or gut mucosa in a negative way, facilitating pathogens to invade into the circulation. We thought that the lower nadir of neutrophil count in the ciprofloxacin group may have been a predisposing factor to fever and infection, sepsis, and death in this study. It is reasonable to assume that patients who got sepsis were at greater risk of death.

Another jeopardizing impact of ciprofloxacin and fluoroquinolone is the emergence of resistant bacteria after its administration as prophylactic antibiotic,3136 but we could not find evidence for this because we were not able to conduct microbiological surveillance in this study. A further limitation was the bitter taste of ciprofloxacin, which might have influenced compliance to take the tablets when the patients were at home. High induction death rate in our study was related to the setting in Dr Sardjito Hospital, where childhood ALL patients were nursed in a general pediatric ward, and lack of supportive care. Occasionally, unavailability of medicines and late initiation of intravenous antibiotic therapy in neutropenic patients with fever also contributed to our high death rate. Due to lack of microbiological data, we could not show the cause of the infective deaths.

Conclusion

The use of ciprofloxacin prophylaxis after chemotherapy in childhood ALL is not warranted in our setting. Further study is needed to determine the rational use of ciprofloxacin in low-income countries and to limit the risk of the occurrence of microbial resistance to this important class of antibiotics.

Acknowledgment

The authors would like to thank the KWF Kankerbestrijding and Estella Fonds from the Netherlands for their excellent financial support for the twinning program between VU University, Amsterdam, the Netherlands and Universitas Gadjah Mada, Yogyakarta, Indonesia, and for their support of research and medication of childhood ALL treatment in Dr Sardjito Hospital, Yogyakarta.

Footnotes

Disclosure

The authors report no conflicts of interest in this work.

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