Recommended for Practice

Antibiotic Prophylaxis in At-Risk Patients

for Prevention of Infection: General

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-…

Systematic Review/Meta-Analysis

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.

Purpose

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

Search Strategy

DATABASES USED: MEDLINE, CANCERLIT, Database of Abstracts of Reviews of Effects, and Cochrane Library (1984–2002); the bibliographies of retrieved studies also were reviewed.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 9 RCTs
  • TOTAL PATIENTS INCLUDED IN REVIEW: 1,202
  • KEY SAMPLE CHARACTERISTICS: Neutropenic patients with cancer

Results

The addition of gram-positive prophylaxis to fluoroquinolones reduced

  • Total episodes of bacteremia by 11.1%
  • Staphylococcal and streptococcal infections
  • Febrile morbidity by 6.7%.


No difference was found between gram-positive prophylaxis and a fluoroquinolone compared with a fluoroquinolone alone with regard to

  • Clinically documented infections
  • Gram-negative infections
  • Unexplained episodes of fever
  • Infectious mortality.


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.

Conclusions

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.

Print

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.

Search Strategy

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.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 19
  • KEY SAMPLE CHARACTERISTICS: The majority of patients had hematologic malignancies. Patients with solid tumor were included in six of the studies.

Results

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.

Print

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.

Search Strategy

DATABASES USED: MEDLINE (1966–1996); the reference lists of retrieved articles also were reviewed.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 18 RCTs
  • TOTAL PATIENTS INCLUDED IN REVIEW: 707
  • KEY SAMPLE CHARACTERISTICS: Patients were undergoing chemotherapy for malignancy (primarily hematologic malignancies). Quinolone prophylaxis was compared with placebo (nine trials) or trimethoprim/sulfamethoxazole (nine trials). The article did not state whether patients received granulocyte colony-stimulating factors.

Results

Without prophylaxis

  • 82% of patients developed fever.
  • 25% of patients developed gram-negative infections.
  • 23% of patients developed gram-positive infections.
  • 55% of patients developed any infection.

Compared with no prophylaxis, quinolone prophylaxis decreased the risk of

  • Gram-negative infections by 79%
  • Gram-negative bacteremia by 77%
  • Microbiologically documented infections by 35%
  • Total infections by 46%
  • Fever by 15%.


Compared with trimethoprim/sulfamethoxazole prophylaxis, quinolone prophylaxis decreased the risk of

  • Gram-negative infections by 70%
  • Gram-negative bacteremia by 68%
  • Microbiologically documented infections by 28%
  • Total infections by 17%.


Quinolone prophylaxis did not affect the rate of

  • Gram-positive infection or bacteremia
  • Fungal infection
  • Clinically documented infection
  • Infection-related death.


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.

Print

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.

Purpose

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

Search Strategy

DATABASES USED: Embase, Medline, PubMed, and Cochrane Collaboration
 
INCLUSION CRITERIA: Patients receiving DC chemotherapy for breast cancer in the adjuvant or neoadjuvant setting, receiving colony-stimulating factors and antibiotics with comparators of prophylactic antibiotics or best supportive care 
 
EXCLUSION CRITERIA: None specified

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 2,200
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane Collaboration risk of bias assessment; one study had high risk, and two had unclear risk of bias; 11 studies were retrospective, and 3 were abstracts only.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 14 
  • TOTAL PATIENTS INCLUDED IN REVIEW = 2,535
  • SAMPLE RANGE ACROSS STUDIES: 30–982

Phase of Care and Clinical Applications

PHASE OF CARE: Active antitumor treatment

Results

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.

Conclusions

FN prophylaxis was associated with lower FN rates; however, the study results could not differentiate the efficacy of antibiotics versus colony-stimulating factors.

Limitations

  • Limited search
  • Mostly low quality/high risk of bias studies
  • Most studies were retrospective.

Nursing Implications

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.

Print

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.

Purpose

STUDY PURPOSE: Analyzing interventions for management of chemotherapy-induced febrile neutropenia in adult patients with cancer.

TYPE OF STUDY: Systematic review

Search Strategy

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

Literature Evaluated

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.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED: 12 
  • TOTAL PATIENTS INCLUDED IN REVIEW: Information not included in the article
  • SAMPLE RANGE ACROSS STUDIES: Adult patients treated for both hematologic and oncologic malignancies with chemotherapy who developed febrile neutropenia during some course of treatment, use of growth factors in this population in some studies as well 
  • KEY SAMPLE CHARACTERISTICS: Adult patients with cancer being treated with chemotherapy, development of febrile neutropenia, treatment with various pharmacologic treatment

Phase of Care and Clinical Applications

PHASE OF CARE: Active anti-tumor treatment

Results

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.

Conclusions

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.

Limitations

  • Limited search
  • Limited number of studies included

Nursing Implications

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.

Print

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.

Purpose

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.

Search Strategy

  • Databases searched from 1996–2011 included MEDLINE, EMBASE, Cochrane databases of controlled trials and cancer network registry of trials, multiple relevant conference proceedings.
  • Regarding keywords, appendices provided extensive detail of exact search terms used per database.
  • Inclusion criteria included patients with cancer and neutropenia from chemotherapy or after bone marrow transplantation. Control groups received placebo, no intervention or an alternate intervention, quasi-randomized controlled trials, or randomized clinical trials (RCTs) for initial review through 2005. An update to 2011 included only RCTs. Exclusion criteria were not stated,.

Literature Evaluated

119 total references were retrieved. Cochrane Handbook for Systematic Reviews methods were used to evaluate and commend on the literature used.

Sample Characteristics

  • 109 total studies were evaluated.
  • 13,579 cases were reviewed.
  • Key characteristics: patients with cancer—sites not specified—but most involved patients with leukemia. Some studies sampled febrile episodes rather than cases.

Phase of Care and Clinical Applications

Active antitumor treatment

Results

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.

Conclusions

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.

Limitations

  • All cause mortality was only available for 47 of the studies. 
  • Length of follow-up in studies may have been too short to fully detect emergence of resistant bacteria. 
  • Most studies were limited to patients with hematologic cancers. 
  • Applicability to patients with solid tumor types requires further study.

Nursing Implications

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.

Print

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.

Purpose

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

Search Strategy

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.

Literature Evaluated

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

Sample Characteristics

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 and Clinical Applications

PHASE OF CARE: Active anti-tumor treatment     

APPLICATIONS: Elder care

Results

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.

Conclusions

Imipenem/cilastatin followed by piperacillin/tazobactam and meropenem had the best performance in the treatment success without modification and all-cause death.

Limitations

  • Low sample sizes
  • Inconsistent definitions of neutropenic fever and treatment success; only included studies of adult patients

Nursing Implications

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.

Print

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.

Purpose

To determine the effectiveness of fluoroquinolone prophylaxis in neutropenic patients with cancer.

Search Strategy

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.

Literature Evaluated

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].

Sample Characteristics

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.

Results

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).

Conclusions

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.

Limitations

There was significant inconsistency between the studies that suggests that additional research is needed.

Nursing Implications

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.

Print

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.

Purpose

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.

Search Strategy

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.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 22 randomized trials
  • KEY SAMPLE CHARACTERISTICS: Patients with cancer undergoing chemotherapy

Results

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.

Print

Research Evidence Summaries

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. 

Study Purpose

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.

Intervention Characteristics/Basic Study Process

Data were collected from retrospective chart review for the use of antibiotics and the incidence and severity of infection.

Sample Characteristics

  • N = 50   
  • AGE: Not provided
  • MALES: Not provided  
  • FEMALES: Not provided
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: All had acute myeloid leukemia. Cases of relapse after hematopoietic cell transplantation were not included.

Setting

  • SITE: Single site   
  • SETTING TYPE: Multiple settings    
  • LOCATION: Vienna

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Pediatrics

Study Design

Retrospective cohort comparison

Measurement Instruments/Methods

  • Febrile neutropenia defined as a temperature greater than 38 degrees C with neutropenia that lasted for an hour, or a single temperature of at least 38.5.
  • Bacterial blood cultures were obtained for patients with fever or other signs of infection.

Results

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.

Conclusions

The findings showed improved outcomes with antibiotic prophylaxis and no apparent rise in VRE isolates with the use of teicoplanin/vancomycin for prophylaxis.

Limitations

  • Small sample (< 100)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Key sample group differences that could influence results
  • The efficacy of the regimen studies was compared to no prophylaxis.
  • There were few cases in which different antibiotics were used.

Nursing Implications

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.

Print

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.

Intervention Characteristics/Basic Study Process

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:

  • Incidence of fever


Secondary endpoints:

  • Type and number of microbiologically-documented infections
  • Use of parenteral antimicrobials
  • Compliance
  • Tolerability
  • Survival 
     

Sample Characteristics

  • 760 hospitalized adult patients with cancer who were expected to develop chemotherapy-induced neutropenia lasting longer than seven days.
  • The sample included patients with the following types of cancer: leukemia, 49%; non-Hodgkin lymphoma or Hodgkin disease, 31%; other hematologic cancers,13%; and solid tumors, 7%.

Setting

  • Inpatient
  • 35 medical centers in Italy

Study Design

the study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial,

Measurement Instruments/Methods

  • Patients were examined daily for signs of infection.
  • In the event of fever or suspected infection, microbiologic cultures were obtained, including at least two separate blood cultures.
  • Infections were classified according to definitions of the European Organisation for Research and Treatment of Cancer ( EORTC).
  • Compliance was determined by counting pills.

Results

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.
 

Conclusions

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.

Limitations

There is concern that routine use of antibiotics is associated with an increase in resistant organisms.

Nursing Implications

The discussion section states that the study provides evidence that prophylaxis is economical because risk of fever is reduced.

Print

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.

Intervention Characteristics/Basic Study Process

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).

Sample Characteristics

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.

Setting

60 oncology centers in the United Kingdom.

Study Design

The study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial with secondary univariate and multivariate analysis.

Measurement Instruments/Methods

  • The primary outcome measure was the incidence of clinically-documented febrile episodes (FEs), defined as a core temperature exceeding 38°C and attributed to infection.
  • The original results demonstrated a reduction in FEs in patients receiving levofloxacin. However, the use of prophylactic antibiotics may increase the rate of antibiotic resistance, so the data from a 2005 study by the authors were analyzed to determine which patients benefit most from prophylactic antibiotics. The analysis measured rates of FEs across all cycles, calculated as the proportion of randomly assigned patients experiencing the event at least once during the chemotherapy program (per patient FE rate). The analysis separates events in cycle 1 because chemotherapy dose reductions and possibly antibiotic resistance may affect later cycles. Per cycle FE rates are calculated as the proportion of observed cycles in which an event occurs.
  • Rates of hospitalization for the treatment of suspected infection (HTSI) also were analyzed. HTSI occurred in a subset of patients with FEs and also in some patients not meeting the trial criteria for an FE.
     

Results

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).

Conclusions

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.
 

Limitations

  • Secondary analysis
  • The primary outcome is the incidence of FEs rather than documented infections, and a reduction in documented infections may be a more meaningful endpoint.
  • The sample is at low risk for febrile neutropenia. An important consideration for low-risk patients with short durations of neutropenia is whether quinolone prophylaxis is of greater benefit than the option of outpatient quinolone treatment for fever and neutropenia, should it occur. Both the National Comprehensive Cancer Network and the Infectious Diseases Society of America recommend oral quinolone-based regimens as outpatient empirical therapy for neutropenic fever in adults meeting criteria for low risk for complications.
  • Use of quinolone prophylaxis may preclude later use of the regimens as empirical therapy for neutropenic fever in the same patient. Guidelines on outpatient management of adults with neutropenic fever assume that quinolones were not used as prophylaxis and the use of quinolones for prophylaxis precludes their use for treatment.
     
Print

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. 

Study Purpose

To study the efficacy of prophylactic antibiotics in pediatric patients with agranulocytosis and to investigate the efficacy and safety of different prophylactic protocols

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 38  
  • MEAN AGE: 8.3 years
  • MALES: 63%, FEMALES: 37%
  • KEY DISEASE CHARACTERISTICS: All had Acute myeloid leukemia (AML) and agranulocytosis after high-intensity chemotherapy

Setting

  • SITE: Single-site    
  • SETTING TYPE: Not specified    
  • LOCATION: China

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Pediatrics

Study Design

Nonrandomized, observational trial

Measurement Instruments/Methods

  • Febrile events defined as a single-axillary temperature > 38.3° centigrade
  • Cultures

Results

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.

Conclusions

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.

Limitations

  • Small sample (< 100)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Measurement validity/reliability questionable
  • Other limitations/explanation: The main outcome measure was a single episode of fever.

Nursing Implications

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.

Print

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. 

Study Purpose

To evaluate the effects of prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML)

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 145   
  • MEDIAN AGE = 58–59 years
  • AGE RANGE = 18–84 years
  • MALES: 67%, FEMALES: 33%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: All had relapsed AML and were undergoing re-induction chemotherapy.
  • OTHER KEY SAMPLE CHARACTERISTICS: Patients on broad spectrum antibiotics or who were receiving other prophylaxis were excluded. Eighteen percent had previously undergone hematopoietic cell transplantation.

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient    
  • LOCATION: Michigan

Phase of Care and Clinical Applications

PHASE OF CARE: Active antitumor treatment

Study Design

Retrospective cohort comparison

Measurement Instruments/Methods

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

Results

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.

Conclusions

Levofloxacin prophylaxis reduced the number of overall infections and the prevalence of gram-negative infections in patients being treated for relapsed or refractory AML.

Limitations

  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)

 

Nursing Implications

The findings suggest that antibiotic prophylaxis is beneficial for patients undergoing re-induction chemotherapy for relapsed or refractory AML.

Print

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.

Study Purpose

To evaluate the impact of quinolone prophylaxis during neutropenia on outcomes including resistance rates and hospital admissions

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 220 patients (141 in ciprofloxacin prophylaxis group, 79 in control group). Some patients were included more than once if more than 30 days passed between episodes of neutropenia. Thus, in 220 patients, 329 episodes of neutropenia occurred (219 in ciprofloxacin prophylaxis group, 110 in control group).
  • AGE: Ciprofloxacin: mean age = 40 years (age range: 14–82 years); Control: mean age = 41 years (age range: 12–66 years)
  • MALES: 60% in ciprofloxacin, 66% in control; FEMALES: 40% in ciprofloxacin, 34% in control
  • KEY DISEASE CHARACTERISTICS: All patients were receiving intensive chemotherapy for a hematologic malignancy or undergoing hematopoietic cell transplantation (HCT). Diseases for ciprofloxacin and control groups, respectively, are primarily blood cancers, including leukemia (44%, 42%), lymphoma (26%, 21%), and multiple myeloma (26%, 28%). Other diseases represented include germ cell tumors and aplastic anemia.
  • OTHER KEY SAMPLE CHARACTERISTICS: More than half of the episodes in each group included patients undergoing autologous or allogeneic HCT. Nearly two-thirds of the episodes in each group included patients with a central venous catheter.

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient   
  • LOCATION: Brazil

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • A retrospective, observational case-control study

Measurement Instruments/Methods

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.

Results

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).

Conclusions

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.

Limitations

  • Risk of bias (no random assignment)
  • Other limitations/explanation: The two cohorts being compared were historical and in different time periods. The authors report no changes in hospital policy or procedures between the two time points; other differences not measured may include different staff or training. Finally, as the data were historical, not all patients included in the cohorts had bacterial samples recovered and saved for further analysis.

Nursing Implications

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.

Print

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.

Study Purpose

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

Intervention Characteristics/Basic Study Process

Administration of prophylactic ciprofloxacin 500 mg twice daily for the prevention of neutropenic fever

Sample Characteristics

  • N = 69   
  • MEAN AGE = 41.3 years (SD = 14.3) ciprofloxacin group, 37.4 years (SD = 9) non-ciprofloxacin group
  • MALES: 68.1%, FEMALES: 31.9%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: AML as diagnosed by bone marrow and peripheral blood smear showing greater than 20% blasts and meeting AML criteria on flow cytometry analysis (criteria for flow cytometry indications of AML not specified)
  • OTHER KEY SAMPLE CHARACTERISTICS: Patients native to Tehran who had been treated from September 2009 to November 2010 for AML with idarubicin 12 mg/m2/day for three days and Ara-C 100–200 mg/m2/day as a continuous infusion for seven days were included.

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient    
  • LOCATION: Tehran, Iran

Phase of Care and Clinical Applications

PHASE OF CARE: Active antitumor treatment

Study Design

Retrospective, medical record, cross-sectional evaluation

Measurement Instruments/Methods

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.

Results

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.

Conclusions

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.

Limitations

  • Small sample (< 100)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Findings not generalizable

Nursing Implications

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.

Print

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. 

Study Purpose

To examine the effects of antibiotic prophylaxis on bacterial infections, antibiotic sensitivity, and nasal and rectal culture findings

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 103 
  • AGE RANGE = 1–21 years, 46% were 10–21 years
  • MEDIAN AGE: 8.7 years
  • MALES: 52.4%, FEMALES: 47.5%
  • KEY DISEASE CHARACTERISTICS: All had acute myeloid leukemia (AML)
  • OTHER KEY SAMPLE CHARACTERISTICS: 73% were Caucasian, 23% African American

Setting

  • SITE: Single site  
  • SETTING TYPE: Multiple settings  
  • LOCATION: St. Judes Hospital

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Retrospective analysis of a previous prospective trial

Measurement Instruments/Methods

  • Infection and febrile neutropenia defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) 3.0
  • Fever–oral temperature of 38º C persisting for one hour, or single oral temperature of 38.3º C
  • Blood stream infection as defined by Centers for Disease Control and Prevention criteria

Results

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.

Conclusions

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.

Limitations

  • Risk of bias (no random assignment)

 

Nursing Implications

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.

Print

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.

Study Purpose

The study focused on the secondary prevention of febrile neutropenia with G-CSF and antibiotics.

Intervention Characteristics/Basic Study Process

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.
 

Sample Characteristics

  • The 48 eligible patients were adults who received chemotherapy for solid tumors and had experienced a prior episode of febrile neutropenia.
  • Patients were scheduled to continue on the same regimen without dose reduction.
  • Most patients were receiving treatment for breast, ovarian, or lung cancer.

Setting

Two sites in Europe.

Study Design

Prospective, randomized pilot trial.

Measurement Instruments/Methods

Patients were evaluated with:

  • Regular complete blood counts
  • Temperature monitoring once daily
  • Observation for adverse effects of the prophylactic antibiotics.

In the event of a fever, the antibiotic prophylaxis was discontinued and a complete clinical evaluation for infection was completed.

Results

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.

Conclusions

G-CSF reduced the risk of febrile neutropenia recurrence. Antibiotics did not provide any additional benefit in terms of prophylaxis.

Limitations

  • Not placebo controlled, not blinded.
  • Patients were not stratified, and the groups were not balanced, particularly by disease and the number of prior chemotherapy cycles.
  • The study was inadequately powered, since the frequency of the outcome measure was close to none (febrile neutropenia episodes).
  • Cost implications were discussed but not in detail.
Print

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.

Study Purpose

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.

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • 95 total patients
  • Patients were aged 3 months to 18 years
  • Patients had acute lymphoblactic leukemia and lymphoma

Setting

A single-site inpatient setting.

Phase of Care and Clinical Applications

  • The phase of care was active antitumor treatment
  • The application was in pediatrics

Study Design

The study was a prospective, double-blind, randomized, placebo-controlled trial.

Measurement Instruments/Methods

  • Bacterial isolation tests for infection sites and rectal swabs.
  • Infections classified as microbiologically documented, clinically documented, or fever of unknown origin.

Results

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).

Conclusions

Ciprofloxacin can prevent fever in neutropenic patients with ALL during the induction phase of chemotherapy with good tolerance and no serious side effects.

Limitations

The small sample (less than 100) was a limitation.

 

Nursing Implications

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.

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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. 

Study Purpose

To compare efficacy and development of bacterial resistance with prophylactic antibiotic regimens of either COT/COL or CIP

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 204  
  • MEDIAN AGE = 62 years
  • MALES: 59%, FEMALES: 41%
  • KEY DISEASE CHARACTERISTICS: All had AML. The majority were receiving induction chemotherapy (61%), and 34% of chemotherapy courses were for consolidation.

Setting

  • SITE: Single site  
  • SETTING TYPE: Inpatient    
  • LOCATION: Germany

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Retrospective

Measurement Instruments/Methods

  • Fever defined at axillary temperature of at least 38º C
  • Infections defined as occurrence of fever and detection of bacterial or fungal pathogens in at least one culture from sterile body sites
  • Pneumonia defined as fever with infiltrates on radiological imaging
  • Common Terminology Criteria for Adverse Events (CTCAE)

Results

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.

Conclusions

Both antibiotic prophylactic regimens resulted in similar patient outcomes, and both appeared to have similar efficacy.

Limitations

  • Risk of bias (no random assignment)

Nursing Implications

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.

Print

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.

Study Purpose

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.

Intervention Characteristics/Basic Study Process

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.
 

Sample Characteristics

  • 80 adult patients made up the sample
  • Female, 35%
  • Male, 65%
  • All had a diangosis of acute leukemia

Phase of Care and Clinical Applications

Active treatment
 

Study Design

Prospective, randomized, placebo-controlled, single-blinded study.

Measurement Instruments/Methods

  • Time to first fever requiring empiric antibiotic coverage
  • In non-neutropenic patients, axillary temperature exceeded 101°F and, in neutropenic patients (absolute neutrophil count of less than 500/mm³), a single oral temperature of 101ºF or higher, or a temperature of 100°F or higher for more than one hour, was taken as a sign of infection or septicemia.
  • Type and number of documented infections
  • Survival at the resolution of neutropenia
  • Compliance
     

Results

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).

Conclusions

This prospective study does not make a strong case for the use of levofloxacin to prevent neutropenic fever in patients with acute leukemia..

Limitations

  • The sample size was small (less than 100).
  • The statistical analysis was not described. It appears that the study is not adequately powered to detect differences between the treatment groups.
  • Levofloxacin prophylaxis was started on day 1 of chemotherapy in this study, rather than after the chemotherapy in anticipation of the chemotherapy nadir, which is the more common practice.
  • The risk of antibiotic resistance is a concern which is not evaluated in this study.
  • This study was conducted in Bangladesh and the authors stated the concern that the hospital environment was not hygienic, so the data may not be applicable to the hospital setting in other countries.
  • The statistical analyses do not appear adequate to use the data to make any definitive recommendations about levofloxacin prophylaxis.
     

Nursing Implications

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.

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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.

Study Purpose

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

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 349 episodes (270 in the tosufloxacin group and 79 in the moxifloxacin group) in 161 patients (116 in the tosufloxacin  group and 45 in the moxifloxacin group)  
  • MEAN AGE = 50.7 years in the tosufloxacin group and 53.5 years in moxifloxacin group
  • MALES: 57.8% in the tosufloxacin group and 57.8% in the moxifloxacin group, FEMALES: 42.2% in the tosufloxacin group and 42.2% in the moxifloxacin group
  • KEY DISEASE CHARACTERISTICS: All patients in the tosufloxacin group and the moxifloxacin group had hematologic malignancies including acute myeloid leukemia (AML) (64.4% and 62%, respectively), lymphoma (9.6% and 10.1%, respectively), acute lymphocytic leukemia (ALL) (15.2% and 5.1%, respectively), and other (10.7% and 22.8%, respectively). More patients had ALL in the tosufloxacin group compared with the moxifloxacin group (p = 0.021). About 7% of patients in both groups were autologous hematopoietic cell transplant recipients.
  • OTHER KEY SAMPLE CHARACTERISTICS: Excluded patients included allogeneic stem cell transplant recipients, patients treated with palliative chemotherapy, patients who had a fever or documented infection at the start of chemotherapy, and patients who received antibiotics five days prior to admission.

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient   
  • LOCATION: Japan

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Retrospective

Measurement Instruments/Methods

  • Fluoroquinolone resistance was determined according to criteria set forth in “Performance Standards for Antimicrobial Susceptibility Testing”, approved by the U.S. National Committee for Clinical and Laboratory Standards.
  • Clostridium difficile-associated diarrhea (CDAD) was defined as a positive Clostridium difficile toxin A assay in the setting of loose stools or watery diarrhea.
  • The diagnostic criteria for proven, probable, and possible fungal infection were based on the revised European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria.

Results

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).

Conclusions

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.

Limitations

  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Other limitations/explanation: The major study limitation is that it's a nonrandomized, retrospective study with data collected from two different time periods (tosufloxacin data from 2004–2006 and moxifloxacin data from 2007–2008). Another potential limitation, although presumed to be minor, is the risk of variation in the degree of patient compliance with oral prophylaxis.

Nursing Implications

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.

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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. 

Study Purpose

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

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 113  
  • MEAN AGE: 4.4 years (range = 0.2–18 years)
  • MALES: 40%, FEMALES: 60%
  • KEY DISEASE CHARACTERISTICS: AML or ALL

Setting

  • SITE: Single-site    
  • SETTING TYPE: Multiple settings    
  • LOCATION: Taiwan

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Pediatrics

Study Design

Retrospective cohort comparison study

Measurement Instruments/Methods

  • Bloodstream infection was defined by the isolation of bacteria from blood cultures and clinical signs of systemic infection.
  • IFI was diagnosed according to the culture or histology of infected tissue.

Results

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.

Conclusions

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.

Limitations

  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)

 

Nursing Implications

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.

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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.

Study Purpose

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.

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N: 120   
  • AGE: Median = 58.6 years (range = 19-80)
  • MALES: 65%  
  • FEMALES: 35%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: AML and MDS
  • OTHER KEY SAMPLE CHARACTERISTICS: N/A

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient    
  • LOCATION: Mayo Clinic, Rochester, MN

Phase of Care and Clinical Applications

PHASE OF CARE: Active anti-tumor treatment

Study Design

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).

Measurement Instruments/Methods

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.

Results

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.

Conclusions

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.

Limitations

  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Other limitations/explanation: Data collected were from only the first episode of FN following antibiotic prophylaxis.

Nursing Implications

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.

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Guideline / Expert Opinion

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.

Purpose & Patient Population

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.

Type of Resource/Evidence-Based Process

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.

Phase of Care and Clinical Applications

Patients were undergoing the active treatment phase of care.

Guidelines & Recommendations

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).

Nursing Implications

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.

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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.

Purpose & Patient Population

To provide guidelines for antimicrobial prophylaxis and management of febrile neutropenia (FN) for adult outpatients with neuropathy.

Type of Resource/Evidence-Based Process

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.

Phase of Care and Clinical Applications

Patients were undergoing the active treatment phase of care.

Results Provided in the Reference

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.

Guidelines & Recommendations

  • Patients should be systematically assessed for risk of FN and/or need for granulocyte colony-stimulating factor prophylaxis.
  • Antimicrobial prophylaxis is recommended only if neutropenia is expected to be profound (absolute neutrophil count [ANC] <100) and more than seven days in duration.
  • Annual influenza immunization is recommended for all patients undergoing chemotherapy and their family members.
  • Drugs of choice are an oral fluoroquinolone for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis.
  • Patients with FN should be assessed using the Multinational Association for Supportive Care in Cancer (MASCC) score or Talcott’s rules to guide whether outpatient treatment is safe. In addition, patients should be compliant, live near the hospital, and have a caregiver and access to transportation at all times.
  • If treating FN as an outpatient, it is recommended to begin empiric antimicrobial treatment within one hour and observe for four hours.
  • Drugs of choice for outpatient empiric treatment of FN are an oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin for those allergic to penicillin).

Limitations

  • Limited data exist from randomized, controlled trials regarding health outcomes or comparing the efficacy and safety of alternative regimens of antimicrobial prophylaxis.
  • The MASCC score revealed a high rate of false-positive results.

Nursing Implications

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.

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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.

Purpose & Patient Population

Patients with chronic lymphocytic leukemia (CLL) were assessed.

Type of Resource/Evidence-Based Process

No process development or search strategy were stated.

Results Provided in the Reference

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.

Guidelines & Recommendations

  • Patients with CLL that are being treated should have appropriate surveillance and examination in regard to assessing for infection, related to their specific treatment therapy. A patient with CLL with a fever should always be considered infected until proven otherwise.
  • Patients receiving frontline fludarabine therapy should receive antiviral prophylaxis with famciclovir 500 mg PO BID, valacyclovir 500 mg PO qid or acyclovir 400 mg PO BID during therapy and for up to six months after therapy. Prophylactic antibiotic or antifungal therapy is not currently recommended for patients receiving fludarabine.
  • Routine anti-infective prophylaxis is not recommended for patients receiving rituximab monotherapy.
  • Routine anti-infective prophylaxis for patients receiving alemtuzumab is recommended, specifically trimethoprim/sulfamethoxazole (TMP/SMX) DS, TIW forprophylaxis against PCP and famciclovir, acyclovir, valacyclovir,or equivalent for antiviral prophylaxis. This therapy should continue for at least two months after treatment ends or until CD4 count recovers to 200 cells/mcl or greater. Patients should also be monitored weekly for CMV using CMV PCR serum assays.
  • Patients who have an absolute neutrophil count (ANC) less than 500 and receiving alemtuzumab should receive G-CSF as prophylaxis.
  • For patients with relapsed or refractory CLL receiving chemo-immunotherapy combination medications, routine incorporation of anti-infective prophylaxis may be necessary to minimize severe infection.
  • If a CLL patient has a history of hepatitis B, prophylaxis with lamivudine 100 mg PO qid should begin four weeks prior to therapy, continue during therapy, and up to six months following therapy.
  • No routine antifungal prophylaxis is recommended for patients with CLL.
  • Patients with CLL should receive PCP prophylaxis with TMP/SMX DS TIW (alternatives are dapsone 100 mg PO five days per week), nebulized pentamadine 300 mg PO, or atovaquone 750 mg PO BID) beginning at the start of therapy and continuing for 6–12 months after therapy or until CD4 count is greater than 250 cells/mcl.
  • Patients with CLL should receive vaccinations with attenuated vaccines.

Limitations

No conflicts of interest were identified.

Nursing Implications

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.

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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 & Patient Population

PURPOSE: To provide guidance for the clinical practice of preventing and treating infection in patients with cancer

Type of Resource/Evidence-Based Process

RESOURCE TYPE: Evidence-based guideline 
 
DATABASES USED: PubMed 2013–2015 for update from prior guideline
 
INCLUSION CRITERIA: English language, clinical trials, guidelines, systematic review, meta-analysis

Phase of Care and Clinical Applications

PHASE OF CARE: Multiple phases of care

Results Provided in the Reference

One thousand one hundred sixty-two publications were retrieved. No method of study quality evaluation or results were reported.

Guidelines & Recommendations

Recommendations include considerations of general antibacterial prophylaxis in patients at intermediate and high risk for infection, considerations of antifungal prophylaxis during neutropenia and for anticipated mucositis, and antiviral prophylaxis with intermediate and high-risk patients. Specific agents are suggested for prophylaxis and treatment in various clinical scenarios. The guidelines outline treatment and diagnostic/assessment approaches for neutropenic fever and specific clinical presentations. They note that chlorhexidine and sliver sulfadiazine-coated short-term central catheters have been shown to decrease the incidence of catheter colonization and bloodstream infections, but not in patients with hematologic malignancies requiring catheters indwelling for about 20 days. The NCCN does not currently endorse the use of a vancomycin lock solution for long-term vascular access devices because of concerns about the emergence of bacterial resistance if widely used. Influenza vaccination with a vaccine that does not have live attenuated organisms can be safely administered, and the guidelines recommend administering the vaccination at least two weeks before a patient receives cytotoxic therapy and annually. Pneumococcal vaccination is recommended in newly diagnosed patients who have not previously received this type of vaccination. HPV vaccination is suggested for patients up to the age of 26. The guidelines provide a recommended vaccination schedule for HVT patients.

Limitations

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.

Nursing Implications

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.

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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.

Purpose & Patient Population

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.

Type of Resource/Evidence-Based Process

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.

Phase of Care and Clinical Applications

  • Patients were undergoing multiple phases of care.
  • The study has clinical applicability for pediatric populations.

Results Provided in the Reference

The volume and highly specific process were not discussed.

Guidelines & Recommendations

Recommendations were made, and possible opportunistic infections at pre-engraftment, post-engraftment, and late phases of HSCT were identified. Recommendations included

  • Antibiotic and antifungal prophylaxis.
  • Consideration of hepatitis B vaccination for those who are hepatitis B-naïve and for donors and recipients of allogeneic transplantation prior to cell collection.
  • Varicella-zoster virus (VZV) vaccination for people in close contact and healthcare providers who are seronegative at least six weeks prior to HSCT contact.
  • Measles, mumps, rubella (MMR) vaccination of those in close contact and healthcare workers.
  • MMR patient vaccination for select groups of patients.
  • Policies that prohibit visits or close contact for people with respiratory or flu-like symptoms.
  • Education to reduce exposure to potential opportunistic infections.
  • Pneumococcal vaccination, annual influenza vaccination, hepatitis B vaccination, consideration of hepatitis A vaccination for people in areas where hepatitis A is endemic, diphtheria vaccination for appropriate age children according to general immunization guidelines, and pertussis reimmunization of appropriate patients.

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.

Limitations

Some recommendations were based on expert opinion due to lack of research evidence in the area.

Nursing Implications

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.

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