Table 3.
Details of Exclusively Pediatric Studies (N = 13)
| First Author [Ref] | Year Published | Study Characteristics | Findings |
|---|---|---|---|
| Fluoroquinolone vs no antibiotic | |||
| Alexander [14] | 2018 | Comparison: Levofloxacin vs no antibiotic Population: AML, relapsed ALL and HSCT Number of patients: 624 Age range: 3–16 years Country: US and Canada Duration of antibiotic prophylaxis: (1) Patients with acute leukemia: 2 consecutive cycles of chemotherapy starting day 1 or 3; (2) HSCT recipients: 1 transplant procedure starting day −2 from stem cell infusion. Prophylaxis continued until: ANC >200/μL after nadir, day 60, or initiation of next chemotherapy cycle Bacteremia frequency in control: AML: 25/63 (40%) Relapsed ALL: 18/36 (50%) Autologous HSCT: 9/78 (12%) Allogeneic HSCT: 27/130 (21%) Systematic surveillance of colonizing organisms tested for resistance: Yes Other: Primary analysis stratified by acute leukemia vs HSCT | Bacteremia: Prophylaxis reduced bacteremia among 195 leukemia patients (RD, 21.6%; 95% CI, 8.8–34.4%) but not among 418 HSCT recipients (RD, 6.3%; 95% CI, .3–13.0%). FN: In both groups combined, prophylaxis reduced FN (RD, 10.8%; 95% CI, 4.2–17.5%). Mortality: No deaths were attributed to bacterial infection. CDI and IFD: Prophylaxis did not increase Clostridium difficile–associated diarrhea (RD, 2.9%; 95% CI, −0.1% to 5.9%) or IFD (RD, −1.0%; 95% CI, −3.4% to 1.5%). Resistance: Qualitatively, higher rate of resistance in bacteremia isolates in prophylaxis compared with control group. Significantly less exposure to aminoglycosides, third- or fourth-generation cephalosporin, and antibiotics commonly used to treat FN in prophylaxis group. |
| Laoprasopwattana [15] | 2013 | Comparison: Ciprofloxacin vs placebo Population: Lymphoma and ALL undergoing induction or consolidation Number of patients: 95 Age range: 0.25–18 years Country: Thailand Duration of antibiotic prophylaxis: Beginning within 5 days after starting chemotherapy and was discontinued when ANC of 1000/μL after 2 weeks of chemotherapy. Median duration of prophylaxis was 18 days in ciprofloxacin group and 10 days in placebo group. Bacteremia frequency in control: 1/50 (2%) Systematic surveillance of colonizing organisms tested for resistance: Patient-level data not reported | Bacteremia: In the prophylaxis group, 2/45 developed bacteremia vs 1/50 receiving placebo. FN and fever: In those who developed neutropenia, prophylaxis reduced the occurrence of fever (RD, −23.0%; 95% CI, −45.0% to −9.0%). In patients with ALL, prophylaxis reduced the occurrence of fever in those undergoing induction (RD, −23.7%; 95% CI, −45.6% to −1.8%), but not in consolidation (RD, 9.8%; 95% CI, −17.8% to 37.5%). CDI and IFD: Not reported. Mortality: Not reported. Resistance: In all 3 cases of bacteremia, the causative organism was susceptible to ciprofloxacin. |
| Widjajanto [16] | 2013 | Comparison: Ciprofloxacin vs placebo Population: Induction ALL Number of patients: 110 Age range: 1–14 years Country: Indonesia Duration of antibiotic prophylaxis: From start of chemotherapy until completion of induction treatment Bacteremia frequency in control: Not reported Systematic surveillance of colonizing organisms tested for resistance: No Other: At baseline, 37/110 were undernourished; abandonment as a reason for induction failure: 10/110 | Bacteremia: Not reported. Fever: In the prophylaxis group, 29/58 had at least 1 fever compared with 17/52 in the placebo group (P = .07). Mortality: In the prophylaxis group, 11/58 died compared with 3/52 in the placebo group (P = .05). CDI and IFD: Not reported. Resistance: Not reported. Other: Clinical sepsis occurred in 29/58 patients receiving prophylaxis and in 20/52 patients receiving placebo (P = .22). |
| Trimethoprim-sulfamethoxazole vs no antibiotic | |||
| Van Eys [17] | 1987 | Comparison: TMP-SMX vs no antibiotic Population: Newly diagnosed ALL Number of patients: 126 Age range: Not reported Country: US Duration of antibiotic prophylaxis: Starting week 5 of therapy and continuing for 3 years or until relapse Bacteremia frequency in control: Not reported Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: Not reported. FN and fever: Not reported. Mortality: One infectious death occurred in each group. CDI and IFD: Not reported. Resistance: Not reported. Other: No effect of prophylaxis on disease-free survival at 3 years. |
| Goorin [18] | 1985 | Comparison: TMP-SMX vs placebo Population: Newly diagnosed ALL (induction, consolidation, early maintenance) Number of patients: 61 Age range: 1–16 years Country: US Duration of antibiotic prophylaxis: Immediately after diagnosis and continued daily during induction, intensification, and early maintenance phases for ~40 weeks Bacteremia frequency in control: Not reported Systematic surveillance of colonizing organisms tested for resistance: Only for patients in the first year of the study due to difficulties collecting routine stool samples | Bacteremia: In the prophylaxis group there were fewer episodes of bacteremia compared with placebo (0 vs 5). FN and fever: Not reported. Mortality: One death occurred in the study and it was due to an infection in the placebo group. CDI and IFD: Not reported. Resistance: In the prophylaxis group, 5/19 patients’ stool surveillance cultures developed gram-negative bacilli resistant to TMP-SMX compared with 0/18 in the placebo group (P = .05). |
| Kovatch [19] | 1985 | Comparison: TMP-SMX vs placebo Population: Induction ALL and AML; relapsed ALL and solid tumors Number of patients: 91 Age range: 0.25–17 years Country: US Duration of antibiotic prophylaxis: Started day 2 or 3 of induction chemotherapy. Continued in the leukemia group until remission and in the solid tumor group until 60 days following chemotherapy initiation. Bacteremia frequency in control: Overall not reported. In the subgroup that developed neutropenia: Induction leukemia: 6/26 (23%) Reinduction leukemia: 0/2 (0%) Solid tumors: 1/7 (14%) Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: Bacteremia reported for the subgroup of patients that developed neutropenia. In this subgroup, 1/39 receiving prophylaxis vs 7/35 in the placebo group developed bacteremia. Fever: In the prophylaxis group 14/43 had a febrile episode compared with 25/48 in the placebo group (P = .10). Mortality: Two infection-related deaths occurred, both in the placebo group. CDI and IFD: No IFD occurred in either group. CDI not reported. Resistance: In the neutropenic subgroup developing bacteremia, the 1 case of bacteremia in the prophylaxis group and 1/7 cases in the placebo group were resistant to TMP-SMX. |
| Lange [20] | 1984 | Comparison: TMP-SMX and nystatin vs no antibiotic Population: Newly diagnosed ALL (induction) Number of patients: 67 Age range: 0.5–16 years Country: US Duration of antibiotic prophylaxis: Not clear Bacteremia frequency in control: 5/25 (20%) Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: In the prophylaxis group, 2/25 developed bacteremia vs 5/35 in the no-antibiotic group. Fever: Not reported. Mortality: There was 1 infection-related death in each group. CDI and IFD: One IFD occurred in the control group. CDI not reported. Resistance: Both cases of bacteremia in the prophylaxis group were resistant to TMP-SMX. No information on the control group. |
| Inoue [21] | 1982 | Comparison: TMP-SMX vs placebo Population: Induction, maintenance and relapsed ALL and AML Number of patients: 102 Age range: Not reported Country: Japan Duration of antibiotic prophylaxis: Not clear Systematic surveillance of colonizing organisms tested for resistance: Yes Bacteremia frequency in control: Not reported | Bacteremia: Narratively reported bacterial sepsis occurred less frequently in the group receiving prophylaxis. Fever: Not reported. Mortality: Not reported. CDI and IFD: Not reported. Resistance: Not reported. |
| Fluoroquinolone vs trimethoprim-sulfamethoxazole | |||
| Cruciani [22] | 1989 | Comparison: Norfloxacin vs TMP-SMX Population ALL, AML, lymphoma, neuroblastoma Number of patients: 44 Age range: Not reported Country: Italy Duration of antibiotic prophylaxis: Children receiving induction remission chemotherapy. Discontinued when neutrophil count exceeded 1000/μL. Bacteremia frequency in control: Not applicable, as prophylaxis control group Systematic surveillance of colonizing organisms tested for resistance: Yes | Bacteremia: In the norfloxacin group, 4/21 developed bacteremia vs 4/23 in the TMP-SMX group. Fever: In norfloxacin group, 9/21 had at least 1 fever vs 20/23 in the TMP-SMX group. Mortality: There was 1 infection-related death in each group. CDI and IFD: Not reported. Resistance: Did not report number of patients with newly developed resistance. |
| Others | |||
| Castagnola [23] | 2003 | Comparison: Amoxicillin/clavulanate vs placebo Population: Leukemia, lymphoma, or solid tumor Number of patients: 167 Age range: 0–18 years Country: Italy Duration of antibiotic prophylaxis: Started when neutropenia developed during chemotherapy. Continued until bone marrow recovery (generally 500–1000/μL). Bacteremia frequency in control: Not applicable, as prophylaxis control group Bacteremia frequency in control: 5/83 (6%) Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: In the prophylaxis group, 3/84 developed bacteremia vs 5/83 in the placebo group. Fever: In the prophylaxis group, 23/84 had fever vs. 31/83 in the group receiving no prophylaxis. Mortality: One death occurred in the study and it was due to an infection in the prophylaxis group. CDI and IFD: Not reported. Resistance: Not reported. |
| Avril [24] | 1994 | Comparison: Ceftazidime and teicoplanin vs no antibiotic Population: Autologous HSCT Number of patients: 60 Age range: 2–16 years Country: France Duration of antibiotic prophylaxis: Started 3–4 days before the onset of aplasia and continued until aplasia resolved. Bacteremia frequency in control: 7/29 (24%) Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: In the prophylaxis group, 2/30 developed bacteremia vs 7/29 in the group receiving no prophylaxis. Fever: In the prophylaxis group, 28/30 had fever vs 29/29 in the group receiving no prophylaxis. Mortality: Not reported. CDI and IFD: Not reported. Resistance: Not reported. |
| Arico [25] | 1992 | Comparison: TMP-SMX daily vs TMP-SMX 3 days a week Population: Maintenance ALL Number of patients: 77 Age range: Not reported Country: Italy Duration of antibiotic prophylaxis: Not clear Bacteremia frequency in control: Not applicable, as prophylaxis control group Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: Not reported. Fever: Not reported. Mortality: Not reported. CDI and IFD: Not reported. Resistance: Not reported. |
| Rossi [26] | 1987 | Comparison: TMP-SMX daily vs TMP-SMX 3 days a week Population: Newly diagnosed and relapsed ALL or AML Number of patients: 97 Age range: 0.9–15 years Country: Italy Duration of antibiotic prophylaxis: For the duration of antineoplastic treatment starting from the first day of induction. Median duration of prophylaxis was 144 days in the daily group and 110 days in the control group. Bacteremia frequency in control: Not applicable, as prophylaxis control group. Systematic surveillance of colonizing organisms tested for resistance: No | Bacteremia: Two episodes of bacteremia in each group. Fever: Not reported. Mortality: Not reported. CDI and IFD: Not reported. Resistance: Not reported. Other: The number of severe infections and side effects were similar between the groups. |
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ANC, absolute neutrophil count; CI, confidence interval; CDI, Clostridium difficile infection; FN, fever and neutropenia; HSCT, hematopoietic stem cell transplantation; IFD, invasive fungal disease; NR, not reported; RD, risk difference; Ref, reference; TMP-SMX, trimethoprim-sulfamethoxazole; US, United States.