Oral Antibiotics vs. Intravenous Antibiotics for Low-Risk Fever and Neutropenia During Cancer Chemotherapy

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Study Was Conducted
• Who Took Part in the Study
• Evaluation Before Antibiotic Therapy
• Key Findings: How Well Each Treatment Worked
• Bloodstream Infections Found Before Treatment
• Fever of Unexplained Origin
• Side Effects and Tolerance
• What This Means for Patients
• Limitations of the Study
• Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• In a study of 232 episodes of fever and neutropenia during cancer chemotherapy, oral antibiotics worked about as well as intravenous antibiotics in low-risk patients.
• Treatment succeeded without any change in the regimen in 71 percent of oral-therapy episodes and 67 percent of intravenous-therapy episodes; the 3 percent difference was not statistically significant.
• Treatment failed more often in the intravenous group because doctors needed to add more antibiotics (32 percent vs. 13 percent).
• Treatment failed more often in the oral group because patients could not tolerate the oral drugs (16 percent vs. 1 percent).
• There were no deaths in either group, but all patients were hospitalized until fever and neutropenia resolved.

Background: Why This Research Matters

During cancer chemotherapy, a fever combined with neutropenia is often the first sign of a potentially life-threatening bacterial infection. Neutropenia is a dangerously low level of neutrophils, a type of white blood cell that fights bacteria. Neutrophils are measured as an absolute neutrophil count, or ANC. Neutropenia is defined as an ANC below 500 polymorphonuclear leukocytes per cubic millimeter.

The standard approach has been to hospitalize these patients right away and start intravenous (IV) broad-spectrum antibiotics. Broad-spectrum means the antibiotics kill many different types of bacteria. However, in more than half of patients treated this way, doctors never find a specific source of infection.

Research suggests that patients with fever and neutropenia can be divided into low-risk and high-risk groups. The main factors are how long neutropenia is expected to last and whether the patient has other serious medical conditions. Examples of conditions that raise risk include low blood pressure (hypotension), lung problems (pulmonary compromise), and abdominal pain.

Low-risk patients are those whose neutropenia lasts no more than 7 to 10 days and who have no other underlying conditions. These patients have fewer medical complications and a lower risk of death than high-risk patients. For this reason, inpatient treatment with IV antibiotics may be unnecessary for low-risk patients. A simpler regimen of broad-spectrum oral antibiotics may be enough.

This study directly compared two approaches in low-risk febrile patients with neutropenia. One approach was standard intravenous monotherapy (a single drug given by vein) with ceftazidime. The other approach was an oral regimen of ciprofloxacin plus amoxicillin–clavulanate. The combination of ciprofloxacin and amoxicillin–clavulanate provides coverage similar to that of ceftazidime. This includes strong activity against Pseudomonas aeruginosa and most other common bacteria that cause fever in patients with neutropenia.

The goal of the study was to determine whether a broad-spectrum oral regimen was an acceptable alternative to intravenous antibiotics in hospitalized low-risk patients.

How the Study Was Conducted

This was a randomized, double-blind, placebo-controlled study. "Randomized" means patients were assigned to a treatment group by chance. "Double-blind" means neither the patients nor the investigators knew which treatment each patient received. "Placebo-controlled" means each active regimen was paired with an inactive preparation, so that every patient received both an oral and an intravenous study agent.

The study ran from May 1992 through July 1997. Patients with cancer who were at least five years of age and who had fever with neutropenia were eligible. Their neutropenia had to be expected to resolve within 10 days after the onset of fever.

Patients were excluded if they had any of the following signs of high risk:

• Hemodynamic instability (unstable blood pressure or circulation)
• Abdominal pain
• Nausea and vomiting
• Diarrhea (passage of six loose stools daily)
• Neurologic or mental-status changes
• Intravascular-catheter infection or catheter-tunnel infection
• A new pulmonary infiltrate (a new shadow on a chest x-ray)

Patients also had to be able to swallow the oral study medications without vomiting. They needed adequate liver function, defined as aminotransferase values less than five times the normal values. They needed adequate kidney function, defined as a creatinine clearance of at least 30 milliliters per minute.

Patients with allergies to any study drug were not eligible. Patients who had received antibiotics within 72 hours before the study began were also not eligible. Prophylactic (preventive) use of acyclovir and trimethoprim–sulfamethoxazole was permitted. All patients, or their parents or guardians, provided written informed consent.

Additional exclusion criteria identified patients at high risk of complications. These included an expected duration of neutropenia longer than 10 days after the onset of infection, or a serious coexisting medical condition. Patients who had undergone autologous stem-cell transplantation were excluded. Patients with human immunodeficiency virus (HIV) infection were excluded. Pregnant patients were excluded.

Certain medications were not permitted during the study. These included calcium- or magnesium-containing oral agents, theophylline, probenecid, and allopurinol. Patients were permitted to receive growth factors and cytokines.

Fever was defined in two ways. A temperature of 38°C or higher on three oral measurements taken 4 hours apart during a 24-hour period counted as fever. A single oral temperature of 38.5°C or higher also counted as fever. Febrile patients whose absolute neutrophil counts were expected to drop below 500 per cubic millimeter within 24 hours after study entry were eligible.

Study Design and Treatment Regimens

A history was obtained and a physical examination was performed on each patient within an hour after presentation. Before empirical therapy began, the following tests were performed:

• Complete blood count
• Blood chemical and coagulation tests
• Chest radiography
• Urinalysis
• Cultures of blood and urine

At least one blood specimen for aerobic and anaerobic cultures was drawn through a catheter lumen, if a catheter was present. Another specimen was drawn from a peripheral vein. In patients with positive blood and urine cultures, cultures were repeated after 48 hours of empirical therapy.

After the initial evaluation, patients were randomly assigned to one of two regimens. The oral regimen consisted of 30 milligrams of ciprofloxacin per kilogram of body weight per day in three divided doses. The maximal dose was 750 milligrams every eight hours. The oral regimen also included 40 milligrams of amoxicillin–clavulanate per kilogram per day in three divided doses. The maximal dose was 500 milligrams every eight hours.

The intravenous regimen consisted of 90 milligrams of ceftazidime per kilogram per day in three divided doses. The maximal dose was 2 grams every eight hours.

Each active regimen was paired with a placebo preparation. This meant that every patient received both an oral and an intravenous study agent. Some patients could not easily swallow tablets because they had mild mucositis (inflammation of the mouth and throat) or were very young. These patients received an equivalent dose of oral amoxicillin–clavulanate or its placebo in liquid form. The oral placebo formulations matched the active drugs. The intravenous placebo solution consisted of 5 percent dextrose plus multivitamins.

Patients continued treatment until neutropenia resolved. Resolution was defined as an increase in the neutrophil count to 500 per cubic millimeter or greater. Once the count recovered to 500 per cubic millimeter, patients with no documented cause of infection could be discharged if they were afebrile (without fever). Patients with documented infections could be switched to appropriate open-label antibiotics. All patients were hospitalized until the fever and neutropenia resolved.

Clinical Assessments and Changes in Treatment

Patients were assessed and complete blood counts were performed daily until the neutropenia resolved. Blood chemical and coagulation values were obtained every third day. Blood was drawn daily for cultures from patients with persistent fever. Chest radiographs were obtained and invasive procedures were performed as clinically indicated.

The initial episode of fever was classified as either unexplained or the result of a clinically or microbiologically defined infection. This classification was based on data gathered within the first 72 hours after study entry.

Changes in treatment regimens followed predefined criteria. These changes were based on the physical examination, microbiologic cultures, and radiography. Any modifications took into account the antimicrobial spectrum of the study drugs, because the investigators did not know which antibiotics each patient actually received.

Antimicrobial agents were added if the patient had clinical or microbiologic evidence of an infection that was presumed or known to be inadequately treated by either study regimen. Vancomycin was added if coagulase-negative staphylococcus was obtained from two pretreatment blood cultures drawn through the intravascular catheter. Vancomycin was also added if gram-positive isolates were obtained from one pretreatment culture. If a gram-negative organism was isolated from blood cultures drawn through the intravascular catheter, the patient was switched to an appropriate open-label regimen of intravenous antibiotics.

Persistent fever alone was not a reason to change treatment, with one exception. Empirical antifungal therapy was added when fever persisted or returned after five days of antibiotics. An antifungal agent or acyclovir was added if there was clinical or microbiologic evidence of invasive fungal infection or herpes simplex virus infection.

Study medications were discontinued and treatment was switched to open-label ceftazidime if patients could not tolerate oral medications. Reasons included mucositis, diarrhea, nausea and vomiting, or rash. When hemodynamic instability, progressive primary infection, or breakthrough infection developed, treatment was changed to a backup regimen. A breakthrough infection was an infection not present at the initial evaluation but detected after 72 hours of study treatment. The backup regimen was imipenem plus gentamicin, or specific antibiotics based on microbiologic results.

How Success and Side Effects Were Measured

Clinical outcomes were defined in advance. Empirical therapy was considered successful if the patient survived the episode of fever and neutropenia without any changes to the assigned regimen. The patient also had to have no evidence of active infection when the neutropenia resolved.

Treatment was considered to have failed in several situations:

• The regimen had to be modified by adding one or more antibacterial, antiviral, or antifungal agents.
• Treatment was changed to the backup regimen for progressive or breakthrough infection.
• Treatment was switched to open-label intravenous antibiotics because of severe mucositis, nausea and vomiting, rash, or diarrhea.

However, treatment was not considered to have failed in patients assigned to intravenous ceftazidime who could not tolerate the oral placebo. These patients continued to receive open-label ceftazidime. These patients were identified after the study assignments were revealed.

Hepatotoxicity (liver damage), nephrotoxicity (kidney damage), and hematologic toxicity (blood-related side effects) were defined according to the Common Toxicity Criteria of the National Cancer Institute. Diarrhea (six loose stools per day) or nausea and vomiting that began after empirical therapy started were considered adverse effects. The protocol specified that all patients 18 years of age or younger should undergo gait and joint assessments by a rheumatologist about every 72 hours during the study.

Statistical Analysis

The study needed 115 episodes of fever and neutropenia in each group. This number gave the study enough statistical power to determine whether the two regimens were equivalent in efficacy. The analysis used an alpha level of 0.20 and a beta error of 0.05. The assumed success rate of standard intravenous therapy was 70 percent. The regimens were considered equivalent if the absolute difference in the proportion of successful outcomes between groups did not exceed 15 percent.

The researchers used the chi-square test or Fisher's exact test to compare outcomes between groups. They used the Wilcoxon rank-sum test to compare continuous variables. They used the Mantel–Haenszel test to compare differences in the duration of fever between groups. They also assessed the statistical independence of data from patients who were enrolled more than once.

Who Took Part in the Study

From May 1992 until July 1997, 211 patients had a total of 284 episodes of fever and neutropenia. Fifty-two episodes were not evaluated, and these were evenly distributed between the two groups. Thirty of these 52 episodes were excluded because of protocol violations. These violations included the addition of antibiotics without approval of study investigators, or the use of prohibited oral medications. Eighteen episodes were excluded because eligibility criteria were found not to have been met after randomization. Four episodes were excluded because patients declined to continue the study.

Among the 232 remaining episodes (in 163 patients), 208 occurred in patients enrolled at the National Cancer Institute. Twenty-four occurred in patients enrolled at the H. Lee Moffitt Cancer Center. Among the 232 patients, 46 were enrolled more than once. Twenty-eight had two episodes, 13 had three episodes, and 5 had four episodes.

There were 116 episodes in each group. There were 84 patients in the group assigned to oral ciprofloxacin and amoxicillin–clavulanate. There were 79 patients in the group assigned to intravenous ceftazidime.

The two groups were similar in age, sex, and type of cancer. The mean age was 42 years in the oral-therapy group and 41 years in the intravenous-therapy group. Ages ranged from 5 to 74 years in the oral group and 8 to 69 years in the intravenous group. Most patients were women with breast cancer. Specifically, 90 of 116 episodes (78 percent) in the oral group and 89 of 116 episodes (77 percent) in the intravenous group involved women.

Regarding cancer type, leukemia or lymphoma accounted for 29 episodes (25 percent) in the oral group and 34 episodes (29 percent) in the intravenous group. Solid tumors accounted for 87 episodes (75 percent) in the oral group and 82 episodes (71 percent) in the intravenous group.

The mean neutrophil count on admission was 81 cells per cubic millimeter in the oral group and 84 cells per cubic millimeter in the intravenous group. A neutrophil count below 100 per cubic millimeter on admission occurred in 91 episodes (78 percent) in the oral group and 87 episodes (75 percent) in the intravenous group. In at least 75 percent of episodes in both groups, patients had an initial neutrophil count of less than 100 per cubic millimeter.

The mean duration of neutropenia was 3.4 days in the oral-therapy group and 3.8 days in the intravenous-therapy group. The range was 1 to 8 days in the oral group and 1 to 14 days in the intravenous group.

In 80 episodes among patients given oral therapy and 90 episodes among patients given intravenous therapy, the affected patients had a central intravascular catheter. Growth factors and cytokines were given to some patients. A granulocyte–macrophage colony-stimulating factor was given during 37 episodes. A granulocyte colony-stimulating factor was given during 163 episodes. An interleukin was given during 4 episodes. No growth factors or cytokines were given during 28 episodes. With the exception of interleukin therapy, which was given in all four cases to patients in the intravenous-therapy group, these treatments were distributed evenly between the two groups.

Evaluation Before Antibiotic Therapy

The cause of about two thirds of all febrile episodes was unexplained. Specifically, fever was unexplained in 79 episodes (68 percent) in the oral-therapy group and 70 episodes (60 percent) in the intravenous-therapy group.

Infection was documented in 32 percent of episodes in the oral-therapy group and 40 percent of episodes in the intravenous-therapy group. Most documented infections were localized and mild or moderate.

The most common documented infections were severe oral or esophageal mucositis. This mucositis developed soon after randomization, prevented swallowing, and was associated with persistent fever in 11 episodes. Oropharyngeal reactivations of herpes simplex virus infections occurred in 23 episodes.

Other types of infections included the following:

• Cellulitis (skin infection) at sites of indwelling central venous catheters or in the limbs or perianal region: 8 episodes in the oral-therapy group and 4 episodes in the intravenous-therapy group
• Urinary tract infections: 8 episodes in the oral group and 5 episodes in the intravenous group
• Sinusitis: 3 episodes in the oral group and 4 episodes in the intravenous group
• Viral upper respiratory tract infections: 3 episodes in each group
• Genital herpes: 3 episodes in each group
• Clostridium difficile enteritis: 1 episode in the oral group and 6 episodes in the intravenous group
• Cecitis (inflammation of the cecum, part of the large intestine): 1 episode in each group

Key Findings: How Well Each Treatment Worked

In the initial analysis performed before the treatment assignments were revealed, the efficacy of the oral and intravenous regimens was similar. Treatment succeeded in 71 percent of oral-therapy episodes and 59 percent of intravenous-therapy episodes. The difference between groups was 11.2 percent, with a 95 percent confidence interval of −1 percent to 24 percent (P=0.07).

After the assignments were revealed, the data were adjusted. The adjustment reflected the fact that ceftazidime therapy was considered successful even if there was intolerance of the oral placebo. In these patients, treatment was "switched" to open-label intravenous ceftazidime. In other words, in nine episodes that were considered before unblinding to have failed, treatment after unblinding was revealed to have succeeded.

Analysis of the adjusted data indicated that treatment was successful in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group. The difference between groups was 3 percent, with a 95 percent confidence interval of −8 percent to 15 percent (P=0.48). This difference was not statistically significant.

Tests of the statistical independence of data from patients enrolled more than once were done. The tests confirmed that the outcome of the first episode had no effect on the outcome of the second episode if the same regimen was used.

Although the overall failure rates were similar in the two groups, the reasons for failure differed. Failure was more likely to result from the need to add antimicrobial agents in the intravenous-therapy group than in the oral-therapy group. This occurred in 32 percent of intravenous episodes versus 13 percent of oral episodes (P<0.001).

Intolerance of the active study drug resulted in failure in 16 percent of episodes treated with oral antibiotics. This compared with 1 percent of episodes treated with intravenous antibiotics (P<0.001). Nausea and vomiting, mucositis, or rash led to discontinuation of the oral regimen. A single episode of rash during infusion led to discontinuation of intravenous ceftazidime.

There were no deaths in either group.

Bloodstream Infections Found Before Treatment

Blood cultures obtained before empirical therapy began were positive in 17 episodes (7 percent). Coagulase-negative staphylococci (five episodes) and Escherichia coli (four episodes) were the predominant bloodstream isolates.

The specific organisms found in blood cultures were as follows:

• Coagulase-negative staphylococcus: 3 episodes in the oral group and 2 episodes in the intravenous group
• Streptococcus: 0 episodes in the oral group and 1 episode in the intravenous group
• Clostridium septicum: 0 episodes in the oral group and 1 episode in the intravenous group
• Enterococcus faecalis: 0 episodes in the oral group and 1 episode in the intravenous group
• Corynebacterium: 0 episodes in the oral group and 1 episode in the intravenous group (this isolate was not Corynebacterium jeikeium)
• Escherichia coli: 1 episode in the oral group and 3 episodes in the intravenous group
• Enterobacter: 0 episodes in the oral group and 1 episode in the intravenous group
• Klebsiella: 1 episode in the oral group and 1 episode in the intravenous group
• Moraxella: 0 episodes in the oral group and 1 episode in the intravenous group
• Acinetobacter: 0 episodes in the oral group and 1 episode in the intravenous group

Blood cultures were positive in a total of 17 episodes. This total includes one multiorganism bloodstream infection in the intravenous-therapy group. That infection involved coagulase-negative staphylococcus and acinetobacter.

Fever of Unexplained Origin

Fever of unexplained origin was successfully treated in 85 percent of episodes in the oral-therapy group (67 of 79 episodes). It was successfully treated in 90 percent of episodes in the intravenous-therapy group (63 of 70 episodes).

In approximately half the episodes in both groups, the fever had disappeared by day 2 of treatment (P=0.65). By day 5, fever had resolved in 90 percent of all episodes.

Clinically significant hypotension (low blood pressure) occurred during three episodes. All three occurred in patients in the intravenous-therapy group. In each case, the hypotension resolved when treatment was switched to the backup regimen. Bacteremia (bacteria in the blood) with cecitis or intraabdominal abscess was the cause of hypotension in two episodes. The other instance of hypotension occurred during a culture-negative episode of fever and neutropenia.

Side Effects and Tolerance

There was a trend toward a higher incidence of intolerance of the active oral antibiotics than of the oral placebo. Intolerance occurred in 16 percent of episodes with active oral antibiotics versus 8 percent with placebo (P=0.07). This difference did not reach statistical significance.

Mucositis was not a common reason for discontinuation of oral medications. There were 44 episodes of fever and neutropenia among patients who had mild mucositis at enrollment. Of these, 9 episodes eventually involved a switch to open-label intravenous therapy. Five of these were in the oral-therapy group and four were in the intravenous-therapy group.

Mucositis developed during four episodes in patients who were asymptomatic on entry. Two of these were in each group. All four required a switch to open-label intravenous ceftazidime.

What This Means for Patients

This study showed that in hospitalized low-risk patients with fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin–clavulanate is safe and effective. The oral regimen produced outcomes similar to those of standard intravenous ceftazidime.

The overall success rates were close: 71 percent for oral therapy and 67 percent for intravenous therapy. This 3 percent difference was not statistically significant, meaning it could have been due to chance. The study was designed to test whether the two regimens were equivalent, and the results supported that conclusion.

The reasons for treatment failure differed between the groups, and this difference matters for patients and doctors. In the intravenous group, doctors more often needed to add antimicrobial agents (32 percent vs. 13 percent). In the oral group, patients more often could not tolerate the drugs (16 percent vs. 1 percent).

There were no deaths in either group. This is an important safety finding for low-risk patients.

For patients, the main practical implication is that oral antibiotics may be a reasonable alternative to intravenous antibiotics in carefully selected low-risk cases. However, the oral regimen carries a higher chance that a patient will not tolerate the medication. Nausea, vomiting, mucositis, or rash were the reasons for stopping the oral regimen.

The study also found that fever resolved quickly in most patients. By day 2, about half of all episodes had no fever. By day 5, fever had resolved in 90 percent of all episodes.

Limitations of the Study

This study enrolled only patients considered to be at low risk of complications. Patients with hemodynamic instability, abdominal pain, nausea and vomiting, diarrhea, neurologic changes, catheter infections, or a new pulmonary infiltrate were excluded. Patients with an expected duration of neutropenia longer than 10 days were also excluded. Therefore, the results do not apply to high-risk patients.

Patients with HIV infection, patients who had undergone autologous stem-cell transplantation, and pregnant patients were excluded. The findings do not apply to these groups.

The study was conducted between May 1992 and July 1997. Treatment practices and antibiotic resistance patterns may have changed since that time.

Fifty-two of the 284 episodes were not evaluated. Thirty of these were excluded for protocol violations, 18 because eligibility criteria were not met after randomization, and 4 because patients declined to continue. This means the final analysis included 232 episodes.

Some patients were enrolled more than once. Forty-six patients had more than one episode. The researchers tested whether repeated enrollment affected the results. They confirmed that the outcome of the first episode had no effect on the outcome of the second episode if the same regimen was used.

The initial analysis, performed before treatment assignments were revealed, showed a success rate of 71 percent for oral therapy and 59 percent for intravenous therapy (P=0.07). After unblinding, the data were adjusted because ceftazidime therapy was counted as successful even when patients could not tolerate the oral placebo. This adjustment changed the intravenous success rate to 67 percent. This adjustment is important to understand when interpreting the results.

Recommendations

Based on this study, the following points may help patients and their care teams:

1. Low-risk patients with fever and neutropenia during cancer chemotherapy may be candidates for oral antibiotic therapy instead of intravenous therapy. Low risk means neutropenia is expected to last no more than 7 to 10 days and no other serious medical conditions are present.
2. Patients should be aware that oral therapy carries a higher chance of intolerance. In this study, 16 percent of oral-therapy episodes failed because patients could not tolerate the drugs, compared with 1 percent of intravenous-therapy episodes.
3. Patients should be aware that intravenous therapy carries a higher chance that doctors will need to add more antibiotics. In this study, 32 percent of intravenous-therapy episodes required added antimicrobial agents, compared with 13 percent of oral-therapy episodes.
4. All patients in this study were hospitalized until fever and neutropenia resolved. Oral therapy in this study was given in a hospital setting, not at home.
5. Patients with high-risk features, such as unstable blood pressure, abdominal pain, nausea and vomiting, diarrhea, neurologic changes, catheter infection, or a new lung infiltrate, were not included in this study. These patients should receive standard intravenous therapy.
6. Patients should discuss with their cancer care team whether they meet low-risk criteria and whether oral antibiotics are an appropriate option for them.

Frequently Asked Questions

What is neutropenia and why does it matter during chemotherapy?

Neutropenia is a dangerously low level of neutrophils, a type of white blood cell that fights bacteria. It is measured as an absolute neutrophil count, or ANC, and is defined as an ANC below 500 polymorphonuclear leukocytes per cubic millimeter. During chemotherapy, a fever combined with neutropenia is often the first sign of a potentially life-threatening bacterial infection.

Who was considered low risk and eligible for this study?

Patients with cancer, at least five years of age, who had fever with neutropenia expected to resolve within 10 days after fever onset. They also needed to swallow oral medications without vomiting, have adequate liver and kidney function, and no allergies to study drugs. Those with high-risk signs such as unstable blood pressure, abdominal pain, nausea and vomiting, diarrhea, neurologic changes, catheter infection, or a new lung infiltrate were excluded.

How well did oral antibiotics work compared with intravenous antibiotics?

In 232 episodes of fever and neutropenia, treatment succeeded without any change in the regimen in 71 percent of oral-therapy episodes and 67 percent of intravenous-therapy episodes. This 3 percent difference was not statistically significant (P=0.48), meaning it could have been due to chance. The study was designed to test whether the two regimens were equivalent, and the results supported that conclusion.

What were the reasons for treatment failure in each group?

Failure was more likely to result from the need to add antimicrobial agents in the intravenous-therapy group than in the oral-therapy group: 32 percent versus 13 percent (P<0.001). Intolerance of the active study drug resulted in failure in 16 percent of episodes treated with oral antibiotics, compared with 1 percent of episodes treated with intravenous antibiotics (P<0.001). Nausea and vomiting, mucositis, or rash led to discontinuation of the oral regimen.

How quickly did fever resolve with treatment?

In approximately half the episodes in both groups, the fever had disappeared by day 2 of treatment (P=0.65). By day 5, fever had resolved in 90 percent of all episodes. Fever of unexplained origin was successfully treated in 85 percent of episodes in the oral-therapy group and 90 percent of episodes in the intravenous-therapy group.

What are the limitations of this study?

The study enrolled only low-risk patients, so results do not apply to high-risk patients. Patients with HIV infection, those who had undergone autologous stem-cell transplantation, and pregnant patients were excluded. The study was conducted between May 1992 and July 1997, so treatment practices and antibiotic resistance patterns may have changed since that time.

If I have low-risk fever and neutropenia during chemotherapy, should I get a second opinion before starting oral antibiotics instead of IV antibiotics?

A second opinion can help confirm you truly meet low-risk criteria before choosing oral antibiotics over intravenous therapy. Low risk means neutropenia is expected to last no more than 7 to 10 days with no other serious medical conditions. High-risk features such as unstable blood pressure, abdominal pain, nausea and vomiting, diarrhea, neurologic changes, catheter infection, or a new lung infiltrate require standard intravenous therapy. Oral therapy carries a higher chance of intolerance, while intravenous therapy more often requires added antibiotics. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: EMPIRICAL ORAL AND INTRAVENOUS ANTIBIOTIC THERAPY FOR LOW-RISK FEBRILE PATIENTS WITH NEUTROPENIA

Authors: Alison Freifeld, M.D., Donna Marchigiani, R.N., Thomas Walsh, M.D., Stephen Chanock, M.D., Linda Lewis, M.D., John Hiemenz, M.D., Sharon Hiemenz, R.N., Jeanne E. Hicks, M.D., Vee Gill, Ph.D., Seth M. Steinberg, Ph.D., and Philip A. Pizzo, M.D.

Author affiliations: National Cancer Institute and Warren Grant Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland; H. Lee Moffitt Cancer Center, University of South Florida, Tampa; and Children's Hospital and Harvard Medical School, Boston.

Publication: The New England Journal of Medicine, Volume 341, Number 5, July 29, 1999, pages 305–311.

Reprint requests: Dr. Freifeld, University of Nebraska Medical Center, Infectious Diseases Section, 985400 Nebraska Medical Center, Omaha, NE 68198-5400.

This patient-friendly article is based on peer-reviewed research.