Antibiotic prophylaxis involves the administration of antibiotics prior to any infection in order to prevent infection. Routine antibiotic prophylaxis has been recommended by several professional groups in patients who are at risk for infection, such as those who have an expected duration of severe neutropenia for more than seven days, and patients undergoing hematopoietic cell transplantation (HCT). Flouroquinolones are most often recommended, and have been associated with decreased incidence of febrile neutropenia and infection. Limited evidence exists regarding the use of quinolones in pediatric patients.
Fluoroquinolone antibiotics can increase the risk of ruptures or tears in the aorta for certain patients (U.S. FDA, 2018b). Fluoroquinolone formulations taken by mouth or given by injection can cause certain mental health side effects and blood sugar level disturbances--the low blood sugar levels can lead to coma (U.S. FDA, 2018a). More information can be found at https://www.fda.gov/drugs/drug-safety-and-availability.
U.S. Food and Drug Administration. (2018a). FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. Retrieved from https://www.fda.gov/drugs/drug-safety-and-availability/fda-reinforces-s…
U.S. Food and Drug Administration. (2018b). FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. Retrieved from https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-…
Cruciani, M., Malena, M., Bosco, O., Nardi, S., Serpelloni, G., & Mengoli, C. (2003). Reappraisal with meta-analysis of the addition of gram-positive prophylaxis to fluoroquinolone in neutropenic patients. Journal of Clinical Oncology, 21, 4127–4137.
To compare prophylaxis with a fluoroquinolone (ciprofloxacin, ofloxacin, perfloxacin, or norfloxacin) in combination with an antibiotic against gram-positive bacteria (penicillins, macrolide, rifampin, or vancomycin) compared to fluoroquinolone alone in neutropenic patients with cancer
DATABASES USED: MEDLINE, CANCERLIT, Database of Abstracts of Reviews of Effects, and Cochrane Library (1984–2002); the bibliographies of retrieved studies also were reviewed.
The addition of gram-positive prophylaxis to fluoroquinolones reduced
No difference was found between gram-positive prophylaxis and a fluoroquinolone compared with a fluoroquinolone alone with regard to
However, adding gram-positive prophylaxis significantly increased the occurrence of side effects, primarily gastrointestinal intolerance and liver function test abnormalities seen with rifampin and roxithromycin.
The authors concluded that the evidence does not support routine use of gram-positive coverage in combination with a fluoroquinolone for antibacterial prophylaxis in neutropenic patients with cancer.
Cruciani, M., Rampazzo, R., Malena, M., Lazzarini, L., Todeschini, G., Messori, A., & Concia, E. (1996). Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: A meta-analysis. Clinical Infectious Diseases, 23, 795–805.
DATABASES USED: MEDLINE was searched for literature published from January 1984–October 1994. Current Contents also was used, as were the bibliographies from MEDLINE articles.
KEYWORDS: Key words used in the search were neutropenia/agranulocytosis and bacterial infections.
INCLUSION CRITERIA: Eligible studies were randomized, controlled trials with fluoroquinolones alone or in combination with gram-positive prophylaxis in granulocytopenic patients receiving chemotherapy for cancer.
Prophylaxis with fluoroquinolones alone was shown to significantly reduce the frequency of gram-negative bacteremia. No significant difference was found in terms of gram-positive bacteremia or infection-related mortality. Fluoroquinolone with gram-positive prophylaxis significantly reduced the frequency of gram-positive bacteremia. Fever-related morbidity and infection-related mortality were not affected. Of note, the majority of the studies (four of six) used fluoroquinolone alone in the control group.
Engels, E.A., Lau, J., & Barza, M. (1998). Efficacy of quinolone prophylaxis in neutropenic cancer patients: A meta-analysis. Journal of Clinical Oncology, 16, 1179–1187.
DATABASES USED: MEDLINE (1966–1996); the reference lists of retrieved articles also were reviewed.
Without prophylaxis
Compared with no prophylaxis, quinolone prophylaxis decreased the risk of
Compared with trimethoprim/sulfamethoxazole prophylaxis, quinolone prophylaxis decreased the risk of
Quinolone prophylaxis did not affect the rate of
The rate of quinolone-resistant gram-negative infections was 3.0%, and the rate of quinolone-resistant gram-positive infections was 9.4% among patients who received quinolone prophylaxis, but no data were provided regarding the rate of quinolone-resistant infections among the control group. Therefore, the effect of quinolone prophylaxis on the rate of quinolone-resistant infections is unknown.
Fernandes, R., Mazzarello, S., Stober, C., Vandermeer, L., Dudani, S., Ibrahim, M.F., . . . Clemons, M. (2016). Optimal primary febrile neutropenia prophylaxis for patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer: A systematic review. Breast Cancer Research and Treatment, 161, 1–10.
STUDY PURPOSE: To determine whether colony-stimulating factors or antibiotic prophylaxis are optimal choices for the prevention of febrile neutropenia in patients receiving docetaxel-cyclophosphamide chemotherapy
TYPE OF STUDY: Systematic review
PHASE OF CARE: Active antitumor treatment
Hospital admission because of febrile neutropenia (FN) occurred in a median of 13% of patients, and 7.5%, on average, had delays in chemotherapy because of FN. DC chemotherapy was associated with median FN rates of 6.6% with and 31.3% without primary prophylaxis.
FN prophylaxis was associated with lower FN rates; however, the study results could not differentiate the efficacy of antibiotics versus colony-stimulating factors.
Patients receiving DC chemotherapy benefit from primary FN prophylaxis. Insufficient evidence exists to determine the comparative efficacy of prophylaxis with antibiotics versus colony-stimulating factors.
Ferreira, J.N., Correia, L.R.B.R., Oliveira, R.M., Watanabe, S.N., Possari, J.F., & Lima, A.F.C. (2017). Managing febrile neutropenia in adult cancer patients: An integrative review of the literature. Revista Brasileira De Enfermagem, 70, 1301–1308.
STUDY PURPOSE: Analyzing interventions for management of chemotherapy-induced febrile neutropenia in adult patients with cancer.
TYPE OF STUDY: Systematic review
DATABASES USED: LILACS (Latin American and Caribbean Literature in Health Sciences), SciELO (Scientific Electronic Library Online), BVS (Virtual Library of Health), PubMed, CINAHL (The Cumulative Index to Nursing and Allied Health Literature), and Web of Science
YEARS INCLUDED: 2010-2015
INCLUSION CRITERIA: Primary articles published in English, Portugese, or Spanish, articles with methodology demonstrating interventions related to the management of chemotherapy-induced febrile neutropenia in adult patients, published between 2010-2015, full-text article availability in the selected databases
TOTAL REFERENCES RETRIEVED: 2,892 articles
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Duplicate articles were first removed from the original 2,892 articles retrieved, followed by elimination of articles that did not cover the research topic, and then finally articles that did not meet the inclusion criteria were removed from the original sample.
PHASE OF CARE: Active anti-tumor treatment
Prophylactic use of colony stimulating factors in patients was effective in avoiding reduction of chemotherapy doses and cycle delays. One of the studies cited use of piperacillin/tazobactam as effective treatment for febrile neutropenia while another one compared ciprofloxacin and cefepime, noting cefepime to be more effective. Neither study reviewed by authors presented a strong case for one antibiotic treatment over another. There were some studies included citing use of biomarkers to classify febrile neutropenia risk in patients and treat prophylactically for those at high risk in the outpatient setting.
Based on the review of these 12 studies, it is evident that the prophylactic use of growth stimulating factors in patients with cancer limits episodes of febrile neutropenia, particularly in diseases such as breast cancer and lymphoma where febrile neutropenia is well documented. There was not a general consensus that could be made for a specific antimicrobial treatment for these patients as many studies cited different medications that deemed effective for patients. Authors note lack of interdisciplinary literature regarding febrile neutropenia guidelines.
Authors cite the need to have nurses, as well as pharmacists and other members of the interdisciplinary team, involved in development of guidelines and protocols as all members of the team treat these patients and need to be knowledgeable about febrile neutropenia.
Gafter-Gvili, A., Fraser, A., Paul, M., Vidal, L., Lawrie, T.A., van de Wetering, M.D., . . . Leibovici, L. (2012) Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database of Systematic Reviews, 1, CD004386.
The purpose of this meta analysis and sytematic review was to evaluate the effect of antibiotic prophylaxis on mortality and infection in neutropenic patients. In addition, subgroups of patients who may benefit the most were identified, and whether or not the effectiveness of different antibiotic regimens were similar was evaluated, as were the adverse effects of different regimens and the emergence of quinolone-resistant bacteria.
119 total references were retrieved. Cochrane Handbook for Systematic Reviews methods were used to evaluate and commend on the literature used.
Active antitumor treatment
Antibiotic prophylaxis resulted in significant reduction in risk of mortality across 46 trials analyzed (RR = 0.66, 95% confidence interval [CI] [0.55, 0.79], p < 0.00001). The greatest effect was with quinolones, although differences between regimens was not statistically significant. The effect was larger for trials in which prophylaxis was begun at the onset of neutropenia. An advantage was seen for all quinolones except for norfloxacin. Antibiotic prophylaxis significantly reduced infection-related mortality (RR = 0.61, 95% CI [0.48, 0.77], p = 0.04), decreased occurrence of fever, documented infection, and occurrence of bacteremia. Quinolones and TMP-SMZ were both associated with side effects that were mostly diarrhea and nausea. TMP-SMZ was associated with drug resistant bacteria cultures (RR = 2.42, 95% CI [1.35, 4.36]). With quinolones, no significant differences were noted between study groups compared to placebo or other interventions. Addition of gram-positive coverage did not show any apparent benefits in terms of mortality.
Findings support use of quinolones as prophylaxis of choice since they reduced risk of death compared to placebo or not intervention and were generally associated with fewer side effects and less resistant bacterial cultures in treated patients. Levofloxacin or ciprofloxacin are recommended.
Prophylactic quinolone antibiotic therapy is recommended for patients with hematologic cancers and those who are likely to develop neutropenia. Additional research is needed to better define patients with solid tumors that may benefit from antibiotic prophylaxis. In most studies, prophylaxis was begun when chemotherapy was initiated, rather than when neutropenia occurred. Prophylaxis should be accompanied by surveillance to monitor quinolone-resistant gram-negative bacteria and other resistant organisms.
Horita, N., Shibata, Y., Watanabe, H., Namkoong, H., & Kaneko, T. (2017). Comparison of antipseudomonal beta-lactams for febrile neutropenia empiric therapy: Systematic review and network meta-analysis. Clinical Microbiology and Infection, 23, 723–729.
STUDY PURPOSE: To compare the effectiveness and safety of antipseudomonal b-lactam empiric monotherapy for febrile neutropenia by network meta-analysis
TYPE OF STUDY: Meta analysis and systematic review
DATABASES USED: PubMed, Cochrane CENTRAL, EMBASE, and Web of Science Core Collection
YEARS INCLUDED: No year limitation
INCLUSION CRITERIA: Definition of febrile neutropenia was ANC less 500 mcl or less than 1,000 mcl and temperature greater than 38 C for more than one hour or temperature greater than 38.3 C. Patients in both arms had to be treated with IV antipseudomonal beta-lactam antibiotic for initial empiric therapy of febrile neutropenia. GCSF use was allowed.
EXCLUSION CRITERIA: Granulocyte transfusion was excluded. Antibiotics not evaluated in a RCT in the past 10 years (since 2006) were excluded.
TOTAL REFERENCES RETRIEVED: 1,275
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Evaluated quality of each study using 6 domains of the Cochrane risk of bias tool
FINAL NUMBER STUDIES INCLUDED: 50 studies
TOTAL PATIENTS INCLUDED IN REVIEW: 10,872 patients
KEY SAMPLE CHARACTERISTICS: Adult and pediatric febrile neutropenia patients undergoing chemotherapy for either solid tumors or hematologic malignancies.
PHASE OF CARE: Active anti-tumor treatment
APPLICATIONS: Elder care
Treatment success without antibiotic modification was most likely with Cefoperazone/sulbactam followed by imipenem/cilastatin, piperacillin/tazobactam, meropenem, cefepime, cefozopran, ceftazidime and panipenem/betamipron. The risk for all-cause death was lowest in all-cause death were lowest in the imipenem/cilastatin arm and highest in the cefepime arm.
Imipenem/cilastatin followed by piperacillin/tazobactam and meropenem had the best performance in the treatment success without modification and all-cause death.
Antipseudomonal antibiotics are effective for empiric treatment of febrile neutropenia and imipenem/cilastatin, piperacillin/tazobactam, and meropenem had the best performance in the treatment success without modification and all-cause death. This may be due to increasing incidence of extended spectrum beta lactamase-producing bacteria that are resistant to cefepime. However, cefepime is still recommended by major guidelines for initial use and remains a reasonable choice, particularly given the concern of antibiotic resistance using carbapenems as initial empiric therapy for febrile neutropenia.
Imran, H., Tleyjeh, I.M., Arndt, C.A., Baddour, L.M., Erwin, P.J., Tsigrelis, C., . . . Montori, V.M. (2008). Fluoroquinolone prophylaxis in patients with neutropenia: A meta-analysis of randomized placebo-controlled trials. European Journal of Clinical Microbiology and Infectious Diseases, 27, 53–63.
To determine the effectiveness of fluoroquinolone prophylaxis in neutropenic patients with cancer.
Databases accessed included MEDLINE, EMBASE, the Cochrane Library (including its database of trials, CENTRAL, and its two databases of systematic reviews, CSDR and DARE), Web of Science, International Pharmaceutical Abstracts Online, and BIOSIS through October 2005. In addition, the reference sections of eligible trials and reviews.
Key words included quinolones, neutropenia, and infection prophylaxis.
To be included, eligible trials met the following criteria: (a) randomized, controlled trial; (b) compared the use of prophylactic fluoroquinolone as a single agent with a placebo; (c) included adults (defined as those at least 16 years of age) who experienced episodes of neutropenia due to cancer chemotherapy and/or hematopoietic stem cell transplantation; and (d) measured the incidence of all-cause mortality and febrile episodes. Randomized, controlled trials published only as abstracts were excluded.
Eight clinical trials with 2,721 patients were evaluated.
One reviewer abstracted the data and two reviewers independently assessed the methodologic quality using established validity criteria. Disagreements were resolved by consensus. A random effects model, the DerSimonian and Laird method, was used for pooling dichotomous data to estimate relative risk and the associated 95% confidence interval. Heterogeneity was analyzed and subgroup analyses were performed. All analyses were performed using RevMan Analyses [v4.2.7].
Three trials included only patients with acute leukemia, two trials included patients with solid tumors, including lymphomas, and three trials included patients with both hematologic and solid malignancies. All studies including patients with hematologic malignancies or hematopoietic cell transplantation were conducted in the inpatient setting and all studies of patients with solid tumors, including lymphoma, were conducted in the outpatient setting. Fluoroquinolone prophylaxis was started at the time of initiation of chemotherapy in five studies, within 4,896 hours of the initiation of chemotherapy or stem cell infusion in two studies, and in one study it varied depending on the expected neutropenia due to a specific regimen (day 5, day 8, or day 15 post-chemotherapy). Prophylaxis duration varied among studies. The fluoroquinolones used in these studies included levofloxacin in two studies, norfloxacin in one study, ciprofloxacin in two studies, ofloxacin in one study, enoxacin in one study, and pefloxacin in one study. The duration of neutropenia was described in four studies and ranged from 2–55 days. It was defined as an absolute neutrophil count (ANC) of less than 500/mm³ in all but one study, in which less than 1,000/mm³ was considered as neutropenia. Compliance was reported to be good or excellent in five out of eight trials. All trials were double-blind. Allocation concealment and the method of randomization were adequate in five trials and unclear in three trials. Intention-to-treat analysis was performed in seven of eight trials.
Fluoroquinolone prophylaxis statistically nonsignificantly decreased all-cause mortality when compared with placebo (3.9% versus 4.5%, RR = 0.76, 95% CI [0.54, 1.08=, p = 0.13). There was no inconsistency in the results between studies (I2 = 0%). Subgroup analyses of studies conducted as inpatient and outpatient also suggested a statistically nonsignificant decrease in mortality with prophylaxis. Compared to placebo, fluoroquinolone prophylaxis resulted in a nonsignificant reduction in the rate of febrile episodes (39% versus 31%, RR = 0.76, 95% CI [0.55, 1.03], p = 0.08). However, there was a large inconsistency in the results between studies (I2 = 95.8%), so additional subgroup analyses were performed. The pooled RR was 0.34 (95% CI [0.14, 0.8]) for the two trials in outpatients and 0.9 (95% CI [0.7, 1.16]) for the six trials conducted in the inpatient setting (p for interaction, < 0.001). The pooled RR was 0.6 (95% CI [0.33, 1.1]) for the two trials that used levofloxacin and 0.89 (95% CI [0.65, 1.22]) for the six trials that used fluoroquinolones other than levofloxacin (p for interaction, 0.01). The RR estimate of 0.76 (95% CI [0.7, 0.83]) from the single inpatient trial that used levofloxacin was possibly different to the estimate from the other inpatient trials (p for interaction, 0.08).
Meta-analysis from eight randomized, placebo-controlled trials demonstrated a statistically nonsignificant decrease in all-cause mortality in neutropenic patients who received fluoroquinolone prophylaxis. The data indicated that fluoroquinolone prophylaxis reduced the risk of febrile episodes in neutropenic outpatients with solid tumors, including lymphomas, but not in hematology inpatients and autologous hematopoietic cell recipients. Patients with solid tumors have a lower risk of febrile neutropenia and are more responsive to prophylaxis. In contrast, hematology inpatients and autologous hematopoietic cell recipients have a high rate of febrile neutropenia and are less responsive to prophylaxis.
There was significant inconsistency between the studies that suggests that additional research is needed.
The data suggested that levofloxacin may be more effective than other fluoroquinolones. Based on the available evidence, there was no significant decrease in all-cause mortality in neutropenic patients who received fluoroquinolone prophylaxis.
van de Wetering, M.D., de Witte, M.A., Kremer, L.C., Offringa, M., Scholten, R.J., & Caron, H.N. (2005). Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: A systematic review of randomized controlled trials. European Journal of Cancer, 41, 1372–1382.
To compare oral-based prophylactic antibiotics (quinolone-based prophylaxis or trimethoprim/sulfamethoxazole (TMP/SMZ)-based regimens) with placebo or no prophylaxis. Trials considering patients with cancer (both adults and children) undergoing chemotherapy in which oral prophylactic antibiotics were started before the expected onset of neutropenia were included.
DATABASES USED: MEDLINE from 1966–October 2002, EMBASE from 1988–October 2002, and the Cochrane Central Register of Controlled Trials, issue 2, 2002; the references were checked for additional articles. Authors of included papers were contacted.
Antibacterial prophylaxis (TMP/SMZ or quinolones) significantly reduced bacteremia by 57% and infection-related mortality. Quinolones significantly reduced the risk of gram-negative bacteremia, but TMP/SMZ did not. TMP/SMZ significantly reduced the risk of gram-positive bacteremia, but quinolones did not. No significant increase was reported in the risk of fungemia or fungal-related mortality with antibacterial prophylaxis. In subgroup analyses, a significant reduction was found in bacteremia in patients undergoing conventional chemotherapy and bone and marrow transplantation.
Boztug, H., Muhlegger, N., Potschger, U., Attarbaschi, A., Peters, C., Mann, G., & Dworzak, M. (2017). Antibiotic prophylaxis with teicoplanin on alternate days reduces rate of viridans sepsis and febrile neutropenia in pediatric patients with acute myeloid leukemia. Annals of Hematology, 96, 99–106.
Report results from using prophylactic outpatient use of teicoplanin or vancomycin for hospitalized patients on febrile neutropenia and bacterial sepsis for cases from 2005–2015. Prior to 2008, no routine antibiotic prophylaxis was used and antibiotics for prophylaxis when used varied. In 2009, a regimen with teicoplanin 15–20 mg/kg IV was instituted, starting at the onset of severe neutropenia on alternate days until the absolute neutrophil count was more than 400/mcl. In hospitalized cases, vancomycin was used. All patients received Pneumocystis jirovecii and systemic antifungal prophylaxis. Colony-stimulating factors were not used.
Data were collected from retrospective chart review for the use of antibiotics and the incidence and severity of infection.
Retrospective cohort comparison
In 98 chemotherapy cycles with teicoplanin or vancomycin prophylaxis, no patients developed viridians sepsis compared to 12 cases of viridians sepsis in patients without prophylaxis (p < 0.0001). Episodes of febrile neutropenia were also fewer in the teicoplanin/vancomycin group (44% versus 82%, p < 0.0001). No appreciable rise in vancomycin-resistant enterococci (VRE) incidence was observed since the regimen had begun.
The findings showed improved outcomes with antibiotic prophylaxis and no apparent rise in VRE isolates with the use of teicoplanin/vancomycin for prophylaxis.
The findings provide support for the benefit of antibiotic prophylaxis in general. Additional research is needed to determine the effects of routine vancomcin/teicoplanin use on the emergence of resistant organisms. Although no such increase was observed in this study, it has been identified in others.
Bucaneve, G., Micozzi, A., Menichetti, F., Martino, P., Dionisi, M.S., Martinelli, G., . . . Del Favero, A. (2005). Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. New England Journal of Medicine, 353, 977–987.
Adult patients with cancer whose chemotherapy-induced neutropenia (absolute neutrophil count [ANC] greater than 1,000) was expected to occur for more than seven days were treated with oral levofloxacin 500 mg or placebo from the start of chemotherapy until the resolution of neutropenia.
Primary endpoint:
Secondary endpoints:
the study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial,
The incidence of fever (axillary temperature 38.5°C or higher, or 38°C at least twice during a 12-hour period) was 65% in the levofloxacin prophylaxis group versus 85% in the placebo group (p = 0.001). Microbiologically documented infection occurred in 22% of patients in the levofloxacin group and 39% of patients in the control group (absolute risk reduction 17%, 95% confidence interval [CI] [24, 10], p < 0.001).
In the levofloxacin group, the incidence of bacteremias (risk reduction 16%, 95% CI [22, 9], p < 0.001) and single-agent gram-negative bacteremias (risk reduction of 7%, 95% CI [10, 2], p < 0.01) was lower.
Death from infection occurred in 2.4% of patients in the levofloxacin group and 3.8% of patients in control group (p = 0.36).
The median duration of prophylaxis was 14 days for patients with solid tumors or lymphoma and 25 days for patients with leukemia.
Overall mortality was 3% in the levofloxacin group and 5% in the placebo group (p = 0.15). Infection-related mortality was 2% in the levofloxacin group and 4% in the placebo group (p = 0.36).
Compliance and reported adverse events were similar in both groups.
The prevalence of fluoroquinolone-resistant bacteremias was 41 of 339 (12%) in the levofloxacin group and 32 of 336 (9.5%) in the control group, but this result was not statistically significant.
The total cost of antibiotics per patient was less in the levofloxacin-treated group. The mean cost of antibiotics was €1,953 in the levofloxacin group and €2,841 in the control group.
Most of the patients had hematologic malignancies, so the study supports the use of antibacterial prophylaxis in this population. However, survival advantage with antibiotic prophylaxis was not demonstrated in the study.
There is concern that routine use of antibiotics is associated with an increase in resistant organisms.
The discussion section states that the study provides evidence that prophylaxis is economical because risk of fever is reduced.
Cullen, M.H., Billingham, L.J., Gaunt, C.H., & Steven, N.M. (2007). Rational selection of patients for antibacterial prophylaxis after chemotherapy. Journal of Clinical Oncology, 25, 4821–4828.
Adult patients with cancer receiving cyclic chemotherapy for solid tumors or lymphoma who were at risk for temporary, severe neutropenia (absolute neutrophil count [ANC] < 500/mm³) were treated with oral levofloxacin 500 mg or matching placebo daily for seven days during the expected neutropenic period. Treatment began on day 5 for regimens associated with early onset of neutropenia (e.g., docetaxel), day 8 for 14-day and 21-day cycles, and day 15 for 28-day cycles.
Patients were on study for a mean of 4.4 cycles of chemotherapy, with 45% of patients completing six cycles.
784 patients were randomly assigned to the placebo arm and received 3,459 cycles of chemotherapy (mean = 4.4 cycles per patient).
Random assignment of patients in the SIGNIFICANT trial was stratified by age (younger than age 40, 40–59, and 60 years of age and older) and cancer type (breast, testicular, small cell lung, Hodgkin disease, non-Hodgkin lymphoma [NHL], and others).
1,565 adults starting chemotherapy for solid tumors or lymphomas; eligible regimens were known to be associated with a risk of neutropenia (ANC < 500/mm³), but were not routinely given with granulocyte–colony-stimulating factor (G-CSF) support. Many different types of cancer were included.
60 oncology centers in the United Kingdom.
The study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial with secondary univariate and multivariate analysis.
119 of 784 (15.2%) control group participants had at least one FE during chemotherapy.
Treatment benefit of quinolone prophylaxis was present across all cycles.
As reported in a 2005 article by the authors, the per-patient FE rate was 10.8% (84 of 781) for patients receiving levofloxacin compared with 15.2% for patients receiving placebo (119 of 784), giving a statistically significant reduction in the risk of FE (odds ratio = 0.67; 95% confidence interval [0.5, 0.91]; p =0.009).
For the first cycle only, the per-patient FE rate was 3.5% in patients receiving levofloxacin compared with 7.9% in controls (odds ratio = 0.42; 95% confidence interval [0.26, 0.66]; p =0.0001), whereas for non–first cycles, the per-patient FE rate was 7.8% (61 of 781) and 9.8% (77 of 784), respectively (odds ratio = 0.78; 95% confidence interval [0.55, 1.11]; p = 0.16).
Per-cycle FE rates in cycle 2 and cycles 2–6 indicate that prophylactic benefit is gained in the small number of patients who experience an FE in cycle 1, but not in the much larger group of patients who do not experience an FE in cycle 1.
The data suggest that the benefit of antibiotics is greatest in those who experience an FE in cycle 1 because they are at higher risk of developing an FE in subsequent cycles compared with patients who do not develop an FE in cycle 1.
Feng, X., Ruan, Y., He, Y., Zhang, Y., Wu, X., Liu, H., . . . Li, C. (2014). Prophylactic first-line antibiotics reduce infectious fever and shorten hospital stay during chemotherapy-induced agranulocytosis in childhood acute myeloid leukemia. Acta Haematologica, 132, 112–117.
To study the efficacy of prophylactic antibiotics in pediatric patients with agranulocytosis and to investigate the efficacy and safety of different prophylactic protocols
Antibiotics included the combination of vancomycin and cefepime or single-use piperacillin/tazobactam. Control patients did not receive antibiotics prophylactically. Both groups were given oral voriconazole to prevent invasive fungal infections.
Nonrandomized, observational trial
There were no differences found between the two preventive protocols used. The prophylactic group had less frequent fever (p < .001), a longer interval to fever (p = .007), and an average of seven fewer hospital days (p < .001). Pulmonary and oral infection were most common. In the prophylactic group, three patients had diarrhea and one patient developed a rash. There were no other antibiotic-related side effects.
There were no differences found between the two preventive protocols used. The prophylactic group had less frequent fever (p < .001), a longer interval to fever (p = .007), and an average of seven fewer hospital days (p < .001). Pulmonary and oral infection were most common. In the prophylactic group, three patients had diarrhea and one patient developed a rash. There were no other antibiotic-related side effects.
The findings showed that prophylactic antibiotics after high-intensity chemotherapy can be effective in children with minimal side effects. Findings should be considered with some caution given the study's limitations.
Ganti, B.R., Marini, B.L., Nagel, J., Bixby, D., & Perissinotti, A.J. (2017). Impact of antibacterial prophylaxis during reinduction chemotherapy for relapse/refractory acute myeloid leukemia. Supportive Care in Cancer, 25, 541–547.
To evaluate the effects of prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML)
Data were obtained from medical records of patients with relapsed or refractory AML admitted from 2006–2015. Standard levofloxacin prophylaxis was begun in 2013 with 500 mg once daily on day 1 of chemotherapy and continued until neutrophil recovery. Cohorts who received levofloxacin were compared to a cohort that did not receive prophylaxis.
PHASE OF CARE: Active antitumor treatment
Retrospective cohort comparison
Febrile neutropenia (FN) was defined as an oral temperature of 38.3 C or greater with and absolute neutrophil count less than 500 cells/mm3
A lower rate of bacteremia existed in the prophylaxis group, but the difference was not significant. The time to onset of bacteremia from onset of neutropenia was delayed in the prophylaxis group compared to others (p = 0.012). No differences in drug-resistant organisms existed between cohorts, or in the incidence of FN. In the prophylaxis group, the frequency of gram-negative organism–related infections was lower.
Levofloxacin prophylaxis reduced the number of overall infections and the prevalence of gram-negative infections in patients being treated for relapsed or refractory AML.
The findings suggest that antibiotic prophylaxis is beneficial for patients undergoing re-induction chemotherapy for relapsed or refractory AML.
Garnica, M., Nouer, S.A., Pellegrino, F.L., Moreira, B.M., Maiolino, A., & Nucci, M. (2013). Ciprofloxacin prophylaxis in high risk neutropenic patients: Effects on outcomes, antimicrobial therapy and resistance. BMC Infectious Diseases, 13, 356.
To evaluate the impact of quinolone prophylaxis during neutropenia on outcomes including resistance rates and hospital admissions
Researchers compared data from hospitalizations during two time periods, representing an intervention group and a control group. The intervention group included patients who received quinolone prophylaxis from 2006–2008. Prophylaxis consisted of 500 mg oral ciprofloxacin twice a day or 200 mg IV twice a day if oral medication was not tolerated. The control group included patients who received no antibiotic prophylaxis during 2005. In the event of a fever, patients in both groups began IV cefepime. If patients had a history of a cefepime-resistant gram-negative infection, they were treated with a carbapenem instead. Analysis of demographics and clinical outcomes, including occurrence of fever, duration of empirical antibiotic therapy, duration of hospitalization, and quinolone resistance, were conducted using SPSS software. Chi-square tests and Mann-Whitney tests were used for categorical and continuous variables, respectively. To evaluate patterns of resistance, data from patients outside the intervention cohort, but also hospitalized from 2006–2008, also were analyzed for resistance.
For their methods, the researchers defined neutropenia as an absolute neutrophil count (ANC) less than 500/mm3. They defined bone marrow recovery as at least two consecutive days with ANC greater than 500/mm3. All blood cultures were processed using a BacT/ALERT® system. Susceptibility tests were completed using the VITEK® automated system. Other laboratory tests on stored bacterial cultures were used to evaluate susceptibility. These included, but were not limited to, disk diffusion, minimal inhibitory concentration, and polymerase chain reaction. Statistical tests, including Chi-square and Mann-Whitney, were completed using SPSS software.
Groups were similar in age and gender. The intervention group was statistically different from the control group in that they experienced slightly shorter periods of neutropenia (9 versus 11 days, p = 0.02), hospitalization (22 versus 24 days, p = 0.002), and antibiotic therapy (8 versus 11 days, p < 0.001); fewer febrile episodes (73 versus 93%, p < 0.001), decreased incidence of any grade mucositis (52% versus 70%, p = 0.003), and bacteremia (22% versus 33%, p = 0.04); and increased use of carbapenem (36% versus 14%, p < 0.001). The intervention group had a higher rate of quinolone-resistant bacteremia (6.77 versus 3.02 per 1,000 patients-day, p = 0.03). Quinolone-resistant enterobacteria was noted in the intervention group and patients outside the intervention cohort but hospitalized during the same time. The rate of extended spectrum beta-lactamase (ESBL)-producing enterobacteria was not significantly increased in the intervention group (0.38 in the control group versus 1.27 in the ciprofloxacin group, p = 0.26).
This study identifies benefits of quinolone prophylaxis in high-risk patients (i.e., patients with hematologic malignancies undergoing chemotherapy with an expected duration of neutropenia longer than seven days, or patients undergoing HCT), including decreased incidence of fever, bacteremia, duration of neutropenia, and length of hospitalization. Risks include an increased incidence of quinolone resistance and bacteremia because of ESBL-producing enterobacteria for the patient and hospital unit.
Quinolone prophylaxis can reduce the incidence of fever, bacteremia, duration of neutropenia, hospitalization, and duration of antibiotic therapy for select high-risk patients. Nurses should understand these benefits and the risk of quinolone resistance for individual patients in the surrounding hospital unit.
Ghadiany, M., Rahimi, H., Rezvani, H., Mohammad Alizadeh, A., Zamani, N., Mehdizadeh, M., & Foratyazdi, M. (2016). Prophylaxis of neutropenic fever with ciprofloxacin in patients with acute myeloid leukemia treated with intensive chemotherapy. Asia-Pacific Journal of Clinical Oncology, 12, e11–e15.
To compare outcomes between patients with acute myeloid leukemia (AML) who did or did not receive prophylactic ciprofloxacin 500 mg twice per day for neutropenic fever
Administration of prophylactic ciprofloxacin 500 mg twice daily for the prevention of neutropenic fever
PHASE OF CARE: Active antitumor treatment
Retrospective, medical record, cross-sectional evaluation
Outcome measurements included rate of neutropenic fever episodes, microbiologic findings, patterns of resistance, and mortality. Independent variables included demographic data, type of AML, and administration or absence of the intervention (prophylactic ciprofloxacin). Administration of granulocyte–colony-stimulating factors were also included in the analyses.
No statistically significant differences were found in any of the outcome variables between patients who received prophylactic ciprofloxacin compared to patients who did not receive the prophylactic treatment. Specifically 80% of the treatment group and 82% of the control had neutropenic fevers. Although mortality rates were lower among those who received the prophylactic ciprofloxacin compared to those who did not, the differences were not statistically significant.
There is no benefit of prophylactic ciprofloxacin for the prevention of neutropenic fever among patients undergoing induction chemotherapy for AML. These findings aligned with other similar studies with the exception of one that the researchers found in the literature.
Understanding the ineffectiveness of prophylactic ciprofloxacin for the prevention of febrile neutropenia in patients undergoing induction chemotherapy for AML can aid in treatment decisions and promote the use of more effective interventions.
Inaba, H., Gaur, A.H., Cao, X., Flynn, P.M., Pounds, S.B., Avutu, V., . . . Rubnitz, J.E. (2014). Feasibility, efficacy, and adverse effects of outpatient antibacterial prophylaxis in children with acute myeloid leukemia. Cancer, 120, 1985–1992.
To examine the effects of antibiotic prophylaxis on bacterial infections, antibiotic sensitivity, and nasal and rectal culture findings
Prophylaxis was outpatient administration of antibacterials after myelosuppressive therapy and the onset of an absolute neutrophil count ≤ 0.5 x 109/L in the absence of fever or other indicators of infection. Prophylaxis was discontinued when the neutrophil count exceeded 0.1 x 109/L. All patients were on a study protocol in which the prophylactic regimens used were amended on an ongoing basis based on short-term findings. In general, patients received IV cefepime every 12 hours, or vancomycin every 12 hours with oral cephalosporin, oral ciprofloxacin, or IV cefepime. All patients received antifungal prophylaxis with voriconazole or echinocandin, pneumocystis prophylaxis, and did not receive colony-stimulating factors. Patients were trained to administer the IV antibiotics. Patients who presented with neutropenia and fever were admitted and treated empirically. Patients had surveillance cultures of the nares and rectum at each admission for detection of resistant organisms. Patients were grouped according to the type of prophylaxis received: A: oral cephalosporin only, B: protocol as described.
Most common infectious events were neutropenia with fever of unknown origin; bloodstream infections; and infections of the skin/mucosa, GI tract, and upper respiratory tract. There was no difference between groups in episodes of fever of unknown origin. Patients who received the full prophylaxis protocol had significantly fewer infectious episodes of any type during induction 1 (p = 0.002), induction 2 (p = 0.0002), and consolidation (p = 0.001). Patients receiving the full vancomycin-based regimen had higher incidence of vancomycin-resistant enterococci (VRE) isolates from surveillance, and three cases also had VRE bacteremia.
Outpatient IV antibiotic prophylaxis was feasible and reduced the incidence of documented infection and bacteremia. Patients receiving vancomycin-based prophylaxis had lower rates of infectious events and had higher incidence of VRE isolates from surveillance.
This study showed that provision of outpatient IV antibiotic prophylaxis to children, administered by their parents, was feasible and effective in reducing infectious events. Findings point to the ongoing need for managing the intensity and duration of prophylaxis to minimize development of resistant bacterial strains.
Lalami, Y., Paesmans, M., Aoun, M., Munoz-Bermeo, R., Reuss, K., Cherifi, S., . . . Klastersky, J. (2004). A prospective randomised evaluation of G-CSF or G-CSF plus oral antibiotics in chemotherapy-treated patients at high risk of developing febrile neutropenia. Supportive Care in Cancer, 12, 725–730.
The study focused on the secondary prevention of febrile neutropenia with G-CSF and antibiotics.
G-CSF (5 mcg/kg subcutaneous) or G-CSF with antibiotics (ciprofloxacin 500 mg by mouth every eight hours and amoxicillin 500 mg by mouth or clavulanate 125 mg by mouth every eight hours) daily starting 48 hours after chemotherapy and continuing until the absolute neutrophil count is greater than 2,000 cells/mm³. Patients were included in the study for one treatment cycle.
Two sites in Europe.
Prospective, randomized pilot trial.
Patients were evaluated with:
In the event of a fever, the antibiotic prophylaxis was discontinued and a complete clinical evaluation for infection was completed.
No episodes of febrile neutropenia occurred in the G-CSF group, and only one incident of febrile neutropenia was reported in the combined group (p = 1). Reported side effects were similar and mild.
G-CSF reduced the risk of febrile neutropenia recurrence. Antibiotics did not provide any additional benefit in terms of prophylaxis.
Laoprasopwattana, K., Khwanna, T., Suwankeeree, P., Sujjanunt, T., Tunyapanit, W., & Chelae, S. (2013). Ciprofloxacin reduces occurrence of fever in children with acute leukemia who develop neutropenia during chemotherapy. Pediatric Infectious Disease Journal, 32(3), e94–e8.
The purpose of the study was to establish efficacy for the use of fluroquinolones in reducing the occurrence of fever in pediatric patients undergoing chemotherapy.
Patients were randomly assigned to receive 10 mg/kg per day of ciprofloxacine orally or placebo twice daily within five days after beginning chemotherapy. Young children who could not take pills were given a liquid form. Axillary temperatures were to be taken every eight hours. Outpatients were seen weekly for evaluation.
A single-site inpatient setting.
The study was a prospective, double-blind, randomized, placebo-controlled trial.
The median duration (IQR) of prophylaxis was longer in the ciprofloxacin group than in the placebo group (18 days [5–30] versus 10 days [3–15], p = 0.031). The number of patients who continued the intervention after discharge from the hospital also was higher in the ciprofloxacin group than in the placebo group (18/45 (40%) versus 10/50). In 71 patients with neutropenia, a lower proportion developed fever in the ciprofloxacin group than in the placebo group (17/34 [50%] versus 27/37 [73%]; absolute difference in risk, -23%; 95% CI [-45%, -0.9%]; p = 0.046). In subgroup analysis of patients with ALL, again the proportion of patients who developed fever was significantly lower in the ciprofloxacin group than in the placebo group (13/24 [54.2%] versus 24/30 [80%], absolute difference in risk, -25.8%; 95% CI [-50.4%, -1.3%]; p = 0.042).
Ciprofloxacin can prevent fever in neutropenic patients with ALL during the induction phase of chemotherapy with good tolerance and no serious side effects.
The small sample (less than 100) was a limitation.
Ciprofloxacin was associated with lower incidence of fever in pediatric patients with neutropenia, and was not associated with significant side effects. There was no difference among patients who did not develop neutropenia. Patients with previous use of flouroquinolones as treatment may be at risk of colonization with flouroquinolone-resistant bacteria, so empiric use in the setting of no neutropenia is not necessarily recommended. Potential adverse effects of flouroquinolone use in children has been identified as a potential concern. This study provides some evidence in this area. Further research of appropriate prophylaxis in pediatric patients with cancer who are at high risk for infection is needed.
Mayer, K., Hahn-Ast, C., Muckter, S., Schmitz, A., Krause, S., Felder, L., . . . von Lilienfeld-Toal, M. (2015). Comparison of antibiotic prophylaxis with cotrimoxazole/colistin (COT/COL) versus ciprofloxacin (CIP) in patients with acute myeloid leukemia. Supportive Care in Cancer, 23, 1321–1329.
To compare efficacy and development of bacterial resistance with prophylactic antibiotic regimens of either COT/COL or CIP
Patients with acute myeloid leukemia (AML) were given antibiotic prophylaxis with either 960 mg cotrimoxazole twice daily and colistin 200 mg three times daily or 500 mg ciproloxacin twice daily. Those receiving CIP were also given cotrimoxazole twice daily two times per week for pneumocystis prophylaxis. All received antifungal prophylaxis. Colony-stimulating factors were given to some patients at the doctor's discretion. Patients receiving CIP did not receive antiviral prophylaxis. Infection-related outcomes were compared between these two cohorts. The study included patients over a four-year span of time. Environmental antimicrobial interventions were standard across both groups.
In both groups, the incidence of febrile neutropenia was about 80%. There were no differences between groups in infections. There were no differences between groups in detection or colonization of resistant organisms. There were no differences between groups in ICU useor differences in mortality related to underlying disease, infection, or septic shock. In both groups, infection was the major cause of death (70%). Overall, 8% of patients died. There were no differences between groups in treatment toxicity.
Both antibiotic prophylactic regimens resulted in similar patient outcomes, and both appeared to have similar efficacy.
Although antibiotic prophylaxis with quinolones is generally preferred, antibiotic prophylaxis with COT/COL was essentially equally effective in this study, and might be considered an effective combination. Some studies have shown increase in quinolone-resistant organisms with standard quinolone prophylaxis. COT/COL prophylaxis may provide an alternative.
Rahman, M.M., & Khan, M.A. (2009). Levofloxacin prophylaxis to prevent bacterial infection in chemotherapy-induced neutropenia in acute leukemia. Bangladesh Medical Research Council Bulletin, 35(3), 91–94.
The purpose of the study was to evaluate if prophylaxis with oral levofloxacin will reduce or delay the febrile neutropenic episodes in chemotherapy-induced neutropenia.
Patients enrolled were assigned randomly to receive 500 mg of levofloxacin orally once daily, or an identical-appearing placebo, starting on day 1 of chemotherapy. Prophylaxis was continued until neutropenia had resolved or fever was documented. Patients were examined daily for clinical signs of infection.
The primary end point of the study was the occurrence of fever, requiring empirical antibacterial therapy during neutropenia. Secondary end points were the type and number of documented infections, the use of parenteral antimicrobial agents during neutropenia, survival at the resolution of neutropenia, compliance, and tolerability.
Active treatment
Prospective, randomized, placebo-controlled, single-blinded study.
Levofloxacin prophylaxis reduced the incidence of fever (17/25 patients (68%) compared to18/23 patients (78%) in placebo group; relative risk = 0.87; absolute difference in risk = 10%, p < 0.001) and reduced the incidence of microbiological proven infection (4/25 [16%] in the levofloxacin group compared to 7/23 [30.4%] in the placebo group; relative risk = 0.52; absolute difference in risk = 14.4%; p < 0.001). However, patients in the levofloxacin group were more likely to have a fever that lasted more than seven days (23%) compared with the control group (12.5%, p not stated).
This prospective study does not make a strong case for the use of levofloxacin to prevent neutropenic fever in patients with acute leukemia..
This study suggests that levofloxacin may reduce fever and infection in patients with acute leukemia. There is a concern regarding antibiotic resistance with the use of prophylactic antibiotics.
Shinohara, A., Yoshiki, Y., Masamoto, Y., Hangaishi, A., Nannya, Y., & Kurokawa, M. (2013). Moxifloxacin is more effective than tosufloxacin in reducing chemotherapy-induced febrile neutropenia in patients with hematological malignancies. Leukemia and Lymphoma, 54, 794–798.
To evaluate the efficacy of antibiotic prophylaxis with tosufloxacin or moxifloxacin in adult patients (aged 16 years or older) with hematologic malignancies who were treated with chemotherapy that induced neutropenia and had an absolute neutrophil count less than 500/mcL for five days or longer
From 2004–2006, patients were treated with prophylactic tosufloxacin 150 mg three times daily, and from 2007–2008, patients were treated with prophylactic moxifloxacin 400 mg daily. All patients in both groups were treated with prophylactic antifungal therapy with either fluconazole or itraconazole.
Comparison of moxifloxacin to tosufloxacin demonstrated a significantly decreased cumulative incidence of febrile neutropenia (74.7% [59 of 79] and 81.1% [219 of 270], respectively, p = 0.044]; increased incidence of fungal infection in the moxifloxacin group (10.1% compared to 4.1% in the tosufloxacin group, p = 0.048); and no cases of CDAD in either group. No significant difference was seen between groups for the mean duration of neutropenia (17.6 days and 17.9 days, respectively, p = 0.853); documented infection (20.3% and 25.9%, respectively, p = 0.373); mortality (0% and 1.9%, respectively, p = 0.592); or fluoroquinolone-resistant infections (7.6% and 9.3%, respectively, p = 0.823). A subgroup analysis of patients with AML showed a higher incidence of febrile neutropenia in the tosufloxacin group (94.1% versus 71.1%, p = 0.013), perhaps related to the observation that the patients with AML had a longer duration of neutropenia (mean = 20.6 days) than the other patients (mean = 13 days) (p < 0.01). A second subgroup analysis showed that moxifloxacin was more effective in preventing febrile neutropenia in patients with neutropenia lasting 15 days or longer (incidence: 73.8% and 89.7%, respectively, p = 0.008) and had no effect on the incidence in patients with neutropenia lasting 14 days or less (p = 0.930).
Moxifloxacin was more effective than tosufloxacin in preventing febrile neutropenia in patients with AML who were most likely to have a longer duration of neutropenia (15 days or longer). No differences in the incidence of documented infections, fluoroquinolone-resistant infections, or overall mortality were observed.
Antibiotic prophylaxis with moxifloxacin is more effective than tosufloxacin in reducing the incidence of febrile neutropenia in high-risk patients who are expected to have a long duration of neutropenia. However, moxifloxacin was associated with more fungal infections. Nurses need to educate and counsel patients regarding antibiotic prophylaxis to enhance adherence, appropriate side effect reporting, and self-monitoring for signs of infection.
Yeh, T., Liu, H., Hou, J., Chen, K., Huang, T., Chang, C., & Liang, D. (2014). Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis. Cancer, 120, 1255–1262.
To investigate the effectiveness of antibiotic and antifungal prophylaxis during intensive chemotherapy for acute leukemia in children and to assess the impact on days of intensive care, changes in antibiotic resistance, and medical cost
Oral ciprofloxacin 300 mg/m2every 12 hours was given when patients became neutropenic and when seven days of neutropenia were expected. Oral voriconazole 4 mg/kg every 12 hours was initiated at the onset of neutropenia in patients with acute myeloid leukemia (AML) and after seven days of neutropenia in patients with acute lymphoblastic leukemia (ALL). IV micafungin was substituted for oriconazole during induction and reinduction chemotherapy. Prophylaxis was discontinued when patients' absolute neutrophil counts recovered to > 100/mcL. Probable invasive fungal infection (IFI) was not included in analysis. Data were analyzed from patients prior to the use of prophylaxis and from patients during the prophylaxis period.
Retrospective cohort comparison study
In the preprophylaxis period, there were 25 episodes of bloodstream infection among 62 patients, and in the prophylaxis period there were five episodes among 51 patients (p < .01). Preprophylaxis, there were 12 episodes of IFI compared to zero episodes during prophylaxis (p < .01). There were fewer episodes of febrile neutropenia with prophylaxis (p = .01). Ciprofloxacin resistance of E-coli Klebsiella pneumoniae, pseudomonas aeruginosa, and serratia marcescens was significantly reduced during the prophylaxis period. Other gram-negative bacilli did not change with regard to ciprofloxacin resistance between the two periods of time. 39% of patients had hepatotoxicity during prophylaxis with micafungin leading to dose modification in three patients and discontinuation in seven patients. Intensive-care stays due to infection and total cost were significantly lower during the prophylaxis period.
Prophylaxis decreased the occurrence of febrile neutropenia, bloodstream infections, IFI, intensive care length of stay due to infection, and cost for patients with ALL and AML. There was no increase in ciprofloxacin resistance associated with prophylaxis with this agent.
This study demonstrates the efficacy of antibiotic and antifungal prophylaxis in children receiving intensive chemotherapy for ALL and AML. There has been limited evidence of prophylaxis use and outcomes in children. Children safely received ciprofloxacin for antibiotic prophylaxis. In this particular study, there was no increase in ciprofloxacin resistant organisms during the time prophylaxis was used; however, analysis was done over a limited period of time and is not seen as conclusive. Continued monitoring for the development of drug resistance is important in organizations providing this type of prophylaxis as a routine. Findings here support the cost effectiveness of prophylaxis, showing lower intensive care stay lengths and overall cost during the time prophylaxis was used.
Yemm, K.E., Barreto, J.N., Mara, K.C., Dierkhising, R.A., Gangat, N., & Tosh, P.K. (2018). A comparison of levofloxacin and oral third-generation cephalosporins as antibacterial prophylaxis in acute leukaemia patients during chemotherapy-induced neutropenia. Journal of Antimicrobial Chemotherapy, 73, 204–211.
To compare the efficacy (measured via incidence of febrile neutropenia [FN]) of levofloxacin versus oral third-generation cephalosporins (OTGCs) given as antibacterial prophylaxis during chemotherapy-induced neutropenia in high-risk patients with hematological malignancies. The goal was to demonstrate non-inferiority of OTGCs as an alternate therapy if fluoroquinolones were contraindicated. Secondary outcomes measured the incidence of bacterial infection between prophylactic drugs and compared the specific microorganisms identified in positive cultures.
Following induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), high-risk patients were prescribed levofloxacin 500 mg daily as antibiotic prophylaxis if appropriate. Similar patients who could not take levofloxacin because of intolerance, allergy, drug interaction, or previous adverse drug reactions were prescribed OTGCs (either cefdinir 300 mg twice daily or cefpodoxime 200 mg twice daily). The duration of antibiotic therapy was not specified. Chart reviews began with the start of antibiotic prophylaxis and continued until the earliest of 30 days following the last dose of antibiotic prophylaxis, the beginning of consolidation chemotherapy administration, or death. The two groups were compared for incidence of FN and for the secondary outcomes.
PHASE OF CARE: Active anti-tumor treatment
Retrospective chart review, matching patients by OTGCs versus levofloxacin in a 1:2 ratio. Matching factors were age (plus or minus 5 years) and the Charlson comorbidity index (plus or minus 3).
Using retrospective chart review, researchers compared the incidence of FN, time to onset of FN, duration of neutropenia, site of infection, morphology of recovered organisms, and resistance to prophylactic agent.
The incidence of FN within 30 days of initiation of antibiotic prophylaxis was 83.4% (95% CI [65.8, 91.9]) in the OTGC group and 92.5% (95% CI [83.8, 96.5]) in the levofloxacin group, and was similar between the two groups (HR = 0.9, 95% CI [0.54, 1.52], p = 0.7). The median duration of neutropenia was also similar between the two groups, with 46 days (IQR = 26-67 days) for OTGCs and 39 days (IQR = 27-49 days) for levofloxacin. Similarly, the duration of prophylaxis prior to the onset of FN was comparable between the two groups (8 days for OTGCs, IQR = 6-12 days; and 8.5 days for levofloxacin, IQR = 5-13.5 days). Patients receiving OTGCs were significantly more likely to require ICU admission than those receiving levofloxacin (p = 0.04). The two groups had no significant differences in site of infection (p = 0.91) and morphology of recovered microorganism (p = 0.74). The OTGC group experienced significantly more cultures positive for Enterobacter (p = 0.043) than the levofloxacin group.
Although antibiotic prophylaxis with levofloxacin demonstrated advantages over OTGCs in the areas of avoidance of ICU admission and avoidance of cultures positive for the Enterobacter microorganism, OTGCs offer an acceptable alternative for those patients in whom fluoroquinolones are contraindicated.
The positive culture site was an implanted central venous catheter in the majority of patients (61.5%). This reinforces the need for nurses to maintain meticulous hand hygiene and infection control practices when working with central venous catheters.
Freifeld, A.G., Bow, E.J., Sepkowitz, K.A., Boeckh, M.J., Ito, J.I., Mullen, C.A., . . . Wingard, J.R. (2011). Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 52, e56-e93.
To provide a guide for the use of antimicrobial agents for chemotherapy-induced fever and neutropenia in patients with cancer. The patient population targeted included adult and pediatric patients with neutropenia.
For this guideline document, the IDSA Standards and Practice Guidelines Committee reconvened many members of their original guideline panel, together with additional experts, in the management of patients with fever and neutropenia. The committee included experts in infectious diseases, oncology, and hematopoietic stem cell transplantation (HSCT) in both adult and pediatric patients. The literature was reviewed and graded according to a systematic weighting of the level and grade of the evidence for making a recommendation.
Patients were undergoing the active treatment phase of care.
Antibiotic Prophylaxis
Fluoroquinolone prophylaxis should be considered for high-risk neutropenic patients (patients expected to have absolute neutrophil counts (ANCs) of 100 cells/mm3 or lower for more than seven days. Levofloxacin and ciprofloxacin are the agents that have been evaluated the most and are generally equivalent, although levofloxacin is preferred for patients at risk for oral mucositis-related invasive viridans group streptococcal infection (B-1). The addition of a gram-positive active agent to fluoroquinolone prophylaxis is not recommended (A-1). Antibacterial prophylaxis is not indicated for low-risk patients anticipated to be neutropenic for less than seven days (A-III).
Antifungal Prophylaxis
Patients at high risk for candida infection, such as recipients of allogeneic HSCT and patients with acute leukemia undergoing intensive chemotherapy, should be treated with antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin (A-I). Patients aged 13 years or older who are undergoing intensive chemotherapy for acute leukemia or myelodysplastic syndrome who are at high risk for aspergillus infection may be treated with posaconazole for antifungal prophylaxis (B-I). Prophylaxis against aspergillus infection is not effective in recipients of pre-engraftment HSCTs, but it is recommended for patients with a prior history of invasive aspergillosis (A-III), anticipated neutropenia of at least two weeks (C-III), or a prolonged period of neutropenia prior to transplantation (C-III). Antifungal prophylaxis is not recommended for patients with an anticipated duration of neutropenia of less than seven days (A-III).
Antiviral Prophylaxis
Herpes simplex virus–positive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I). Annual influenza vaccination is recommended for all patients being treated for cancer (A-II). The optimal timing has not been established, but serologic responses may be best between chemotherapy cycles (more than seven days after the last treatment) or more than two weeks prior to the start of therapy (B-III).
Colony-Stimulating Factors
Colony-stimulating factors are recommended for prophylaxis against neutropenia when the anticipated risk of fever and neutropenia is 20% or greater.
Prevention of Catheter-Related Bloodstream Infections
Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine are recommended for all central venous catheter insertions (A-I).
Hand Hygiene
Hand hygiene is the most effective means of preventing infection in the hospital (A-II).
Environment
HSCT recipients should be in private rooms (B-III). Patients with neutropenia do not need to be placed in single-patient rooms. Allogeneic HSCT recipients should be in rooms with more than 12 air exchanges, high-efficiency particulate absorption filtration, and positive pressure (A-III). Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III).
Isolation and Barrier Precautions
No specific protective gear (gowns, gloves, or masks) are necessary during the routine care of neutropenic patients. Standard barrier precautions should be used for all patients when contact with body fluids is anticipated.
Food
In general, food should be well cooked. Well-cleaned uncooked fruits and vegetables are acceptable.
Skin and Oral Care
Daily showers are recommended to maintain skin integrity (expert opinion). Patients should brush their teeth two times per day or more with a regular toothbrush, and flossing can be performed if it can be performed without trauma (expert opinion). Patients with mucositis should rinse their mouths with sterile water, saline, or sodium bicarbonate rinses four to six times per day (expert opinion). Menstruating immunocompromised women should avoid tampons (expert opinion). Rectal thermometers, enemas, suppositories, and rectal examinations are contraindicated for patients with neutropenia (expert opinion).
This was a comprehensive guideline developed by the Infectious Diseases Society of America (IDSA) to guide clinicians in the care of patients with chemotherapy-induced neutropenia and in the management of febrile neutropenia. The full guide can be located at http://cid.oxfordjournals.org/content/52/4/e56.full.
Flowers, C. R., Seidenfeld, J., Bow, E. J., Karten, C., Gleason, C., Hawley, D. K., . . . Ramsey, S. D. (2013). Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy. Journal of Clinical Oncology, 31, 794–810.
To provide guidelines for antimicrobial prophylaxis and management of febrile neutropenia (FN) for adult outpatients with neuropathy.
The resource was a consensus-based guideline. A literature search examined articles indexed in MEDLINE (January 1987–April 2011). A systematic review of 47 articles from 43 studies were included in the analysis. Keywords included terms for malignant diseases; terms for neutropenia, infection, or fever; and terms for clinical guidelines, systematic reviews, meta-analyses, or clinical trials.
Articles were included if they were fully published English language reports on the topics of antimicrobials for the prevention of infection in neutropenic outpatient patients with cancer (with or without fever), direct comparisons of outcomes between inpatient and outpatient management of FN in patients with cancer, and methods to quantify risk of complications in patients with cancer and FN. Articles were excluded if they were meeting abstracts, commentaries, letters, editorials, case reports, and nonsystematic reviews.
Patients were undergoing the active treatment phase of care.
A table of recommendations addressed three main areas of concern: (a) preventing infection in patients at risk for neutropenia undergoing chemotherapy, (b) identifying which patients with cancer and FN may be safely treated as outpatients, and (c) identifying interventions for the outpatient management of FN.
These guidelines help clinicians determine which patients require hospitalization and which can safely be treated in the outpatient setting. The guidelines also aid in selecting appropriate antimicrobial prophylaxis for neutropenic patients.
Moran, M., Browning, M., & Buckby, E. (2007). Nursing guidelines for managing infections in patients with chronic lymphocytic leukemia. Clinical Journal of Oncology Nursing, 11, 914–924.
Patients with chronic lymphocytic leukemia (CLL) were assessed.
No process development or search strategy were stated.
Information was provided by the authors in regards to current trends in CLL treatment and the risk of infection that is present with the most common current treatments, such as fludarabine, rituximab, alemtuzumab, and steroids. Specific bacterial and fungal infections that are most commonly associated with treatment were discussed as well as the prevention and management of these infections. A table was provided that had the most commonly occurring infections; chemotherapy treatment most commonly associated with each infection, prophylaxis, treatment options for the infection with duration and side effects; and nursing interventions. Discussion also was included on monoclonal antibodies and risk of opportunistic infection due to immune incompetency from these agents.
No conflicts of interest were identified.
Combinations of antibacterial, antiviral, and antifungal prophylactic medications may be appropriate in patients with CLL being treated with various chemotherapy regimens to prevent a life threatening infection from occurring and the type and duration is dependent on the agents they are receiving.
National Comprehensive Cancer Network. (2016). NCCN Clinical Practice Guidelines in Oncology: Prevention and treatment of cancer-related infections [v. 2.2016]. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf
PURPOSE: To provide guidance for the clinical practice of preventing and treating infection in patients with cancer
PHASE OF CARE: Multiple phases of care
One thousand one hundred sixty-two publications were retrieved. No method of study quality evaluation or results were reported.
The combination of evidence- and consensus-based recommendations and the differentiation between them are not clearly stated. For vascular access device prevention of infection, the guidelines only address antimicrobial-coated catheters and not any other aspect of management.
The guidelines provide a comprehensive reference to assess patient risk of infection and expert recommendations regarding interventions aimed at the prevention and treatment of infection in patients with cancer. They do not discuss long-term survivorship issues in this area.
Tomblyn, M., Chiller, T., Einsele, H., Gress, R., Sepkowitz, K., Storek, J., . . . Centers for Disease Control and Prevention. (2009). Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biology of Blood and Marrow Transplantation, 15, 1143–1238.
To update previously published guidelines from 2000 for the prevention of infection in patients receiving any type of hematopoietic stem cell transplantation (HSCT). Patients analyzed were adults and pediatric populations receiving allogeneic or autologous HSCT.
The resource was presented as an evidence-based guideline. An international group of experts from identified professional organizations reviewed and graded evidence and developed recommendations.
The volume and highly specific process were not discussed.
Recommendations were made, and possible opportunistic infections at pre-engraftment, post-engraftment, and late phases of HSCT were identified. Recommendations included
Timing and appropriate individuals for various immunizations are important considerations, and it is recommended that users of this information refer to the full report. Overall, use of live vaccines is contraindicated for these patients; vaccination is contraindicated in those with chronic graft-versus-host disease or when patients are still immunosuppressed.
Some recommendations were based on expert opinion due to lack of research evidence in the area.
Specific interventions for prevention of infection among HSCT recipients is a complex field, and healthcare providers who work with these patients need to be aware of current knowledge. Evidence in this area continues to evolve as HSCT techniques change and further evidence is gained regarding the immediate and long-term effects of HSCT.