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Fluoroquinolone prophylaxis in chemotherapy-induced neutropenia
Two trials found promising results with the prophylaxis, but potential disdvantages do exist.
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Chemotherapy-induced neutropenia is a complication of cancer treatment that has many consequences for the patient. The incidence of death from neutropenic fevers and sepsis is estimated to be about 5% to 10% in the cancer population, but is higher in certain patients such as those with invasive fungal infections and other comorbid conditions. This incidence is lower than the about 50% rate seen two or three decades ago. Other complications include the need for hospitalization, modification of subsequent chemotherapy doses, reduction in the patient’s quality of life and higher treatment costs. Chemotherapy-induced neutropenia is the most important dose-limited adverse effect for most chemotherapy regimens.
Some patients are at higher risk for neutropenic fevers. These include older people, patients with hematologic cancers, those with a more advanced stage of cancer and those who experience neutropenia during the first cycle of chemotherapy.
Certain chemotherapy regimens and chemotherapy doses are more likely to cause neutropenia. Although it seems counterintuitive, neutropenic fevers are more likely to occur in the first cycle of chemotherapy compared with later cycles. Furthermore, those patients who do experience chemotherapy-induced neutropenia in the first cycle are more likely to experience it in later cycles compared with patients who do not have chemotherapy-induced neutropenia in the first cycle.
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Neutropenia prevention
Strategies to prevent neutropenic fevers include methods to prevent the neutropenia, such as the use of colony-stimulating factors (filgrastim, pegfilgrastim and sargramostim). Another strategy is to prevent the infection by using antibiotics and antifungal medications. To be effective, antibiotics need to be tailored to the most likely bacterial infections.
Two decades ago, the most likely pathogens associated with neutropenic fevers were gram-negative organisms like Escherichia coli, Klebsiella and Pseudomonas. The majority of identified pathogens are gram-positive organisms like Staphylococcus, Streptococcus and Enterococcus species. In addition, polymicrobial infections and infections with resistant organisms like methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and extended-spectrum beta-lactamase–producing organisms are more common.
About 20 years ago, research was conducted using trimethotrim/sulfamethoxazole (TMP/SMZ) to prevent neutropenic fevers. This agent showed good activity but has adverse effects that include rash, nausea/vomiting and prolonged neutropenia. Unfortunately, the sensitivities of important organisms to TMP/SMZ have declined over the years. Subsequently, the fluoroquinolone antibiotics have been studied to prevent chemotherapy-induced neutropenia. These broad-spectrum antibiotics have shown better activity and, especially with the newer fluoroquinolones, have good coverage of gram-positive organisms. The fluoroquinolones also have excellent oral bioavailability and are well tolerated by most patients.
Ciprofloxacin was the first fluoroquinolone studied for chemotherapy-induced neutropenia. It is dosed as 500 mg orally twice daily, with the dose adjusted for patients with decreased renal function. Ciprofloxacin may have a theoretical advantage for pseudomonas coverage and it is inexpensive.
Levofloxacin, a second generation fluoroquinolone, has been studied more recently for chemotherapy-induced neutropenia. This agent is dosed as 500 mg orally daily, and the dose should be adjusted for reduced renal function. Levofloxacin has better coverage for gram-positive organisms but it is more expensive than ciprofloxacin (although not prohibitively so).
Both fluoroquinolone agents are better tolerated with a low incidence of nausea, rash and hyper/hypoglycemia. Levofloxacin has been studied in two recent trials to prevent infection and hospitalization and other complications from chemotherapy-induced neutropenia.
SIGNIFICANT trial
In the SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/– Antibiotic in a Number of Tumours) trial, conducted by Cullen and associates, the patient population included patients with solid tumors and lymphoma receiving chemotherapy that was likely to cause neutropenia but which was not routinely administered with granulocyte colony–stimulating factor. The exclusion criteria included patients with active infections or those receiving current antibiotics, those patients who were to receive G-CSF, and those patients with a creatinine clearance ,40 mL/minute. Participants were stratified according to age, tumor type and treatment center. The treatment included levofloxacin 500 mg orally daily for seven days or placebo. The treatment period was timed to coincide with the predicted neutropenic period. Table 1 describes the main treatment outcomes for both arms of the study.
The researchers concluded that prophylactic treatment with levofloxacin reduced the incidence of fever, infection and the need for hospitalization in this patient population. The treatment was well tolerated with only minor gastrointestinal symptoms and rash reported.
GIMEMA trial
In the GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell’ Adulto) trial, conducted by Bucaneve and associates, levofloxacin prophylaxis was studied in patients with acute leukemia, lymphomas and solid tumors. About half the patients in the trial had acute leukemia. All patients were expected to have neutropenia that was to last at least seven days. Exclusion criteria included allogenic stem cell transplant, treatment with antibiotics within the previous five days and documented infections. The treatment consisted of levofloxacin 500 mg orally daily for seven days (timed to the period of expected neutropenia) or placebo. The treatment groups were stratified according to type of cancer and treatment center. Table 2 shows the primary outcome data from this trial.
The researchers concluded that levofloxacin prophylaxis reduced the risk for all fever and infection outcomes. The significant effect of levofloxacin was evident both in acute leukemia as well as in patients with lymphoma/solid tumors. There was a reduction in gram-positive as well as gram-negative bacteremias.
The prophylaxis was cost effective, with the levofloxacin-treated group having a much lower total cost of antibiotic therapy.
In a separate analysis (conducted by Leibovici) based on the results from these two trials as well as other data, the number needed to treat to prevent death from any cause ranged from 24 to 132. The number needed to treat to prevent fever was much lower, ranging from four to 23. These low number-needed-to-treat values further show the value of levofloxacin prophylaxis.
Potential problems
The potential disadvantages of fluoroquinolone prophylaxis include cost, adverse effects and the development of bacterial resistance. The cost of fluoroquinolone therapy is minimal, especially compared with the cost of a fever-workup, hospitalization or broad-spectrum IV antibiotics. The adverse effects are also minimal with fluoroquinolone therapy being well tolerated.
The development of fluoroquinolone-resistant organisms is a more important potential problem. In published data, there has not been a significant increase in fluoroquinolone-resistant infections in study participants. There have been reports of increasing fluoroquinolone-resistant organisms in the general population, but the use of fluoroquinolone prophylaxis in cancer patients is an insignificant amount compared with the use in the general population.
There have been reports of rising fluoroquinolone-resistance in inpatient hospital cancer units. However, these trials still show the total therapeutic value of using this therapy. In addition, successful prophylaxis would decrease the use of IV broad-spectrum antibiotics that by themselves can increase bacterial resistance.
The value of levofloxacin prophylaxis was demonstrated in a discontinuation trial conducted by Reuter and associates. The effect of fluoroquinolone prophylaxis was measured before, during and after a planned discontinuation of fluoroquinolone prophylaxis to be able to study the reversibility of the fluoroquinolone resistance that was seen at this university hospital study location. Table 3 shows the data from the three phases of this study.
The second phase of the trial (with no fluoroquinolone prophylaxis) was halted early due to the dramatic increases in gram-positive and gram-negative bacteremias, sepsis and death due to infection, although the number of patients in the second phase was low. In this study the findings demonstrated the continued value of levofloxacin prophylaxis despite some level of fluoroquinolone resistance.
The patients most likely to benefit from levofloxacin prophylaxis include patients with acute leukemia or bone marrow transplantation and those patients with solid tumors or lymphoma receiving their first cycle of chemotherapy likely to cause neutropenia.
Lisa K. Lohr, PharmD, is Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is the Pharmacology Section Editor of the HemOnc Today Editorial Board.
For more information:
- Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353:977-987.
- Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005;353:988-998.
- Leibovici L, Paul M, Cullen M, et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer. 2006;107:1743-1751.
- Reuter S, Kern WV, Sigge A, et al. Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. Clin Infect Dis. 2005;40:1087-1093.