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Rifampin Does Not Improve the Efficacy of Quinolone Antibacterial Prophylaxis in Neutropenic Cancer Patients: Results of a Randomized Clinical Trial

From the Division of Medical Oncology, Microbiology, and Infectious Disease, Hospital Universitario "12 de Octubre," Madrid, and Division of Medical Oncology, Hospital Universitario San Pau i Santa Creu, Barcelona, Spain.

Address reprint requests to Manuel Hidalgo, MD, Institute for Drug Development, 8122 Datapoint Drive Suite 700, San Antonio, TX 78229; email mhidalgo{at}saci.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine whether the addition of rifampin to a quinolone-based antibacterial prophylactic regimen in patients undergoing high-dose chemotherapy (HDC) with peripheral-blood stem-cell transplantation (PBSCT) decreases the incidence of neutropenia and fever, Gram-positive bacteremia, and infection-related morbidity.

PATIENTS AND METHODS: Patients with solid tumors undergoing HDC with PBSCT were randomized to receive prophylactic antibiotics with either ciprofloxacin 500 mg orally every 8 hours or the same ciprofloxacin regimen with rifampin 300 mg orally every 12 hours. Prophylaxis was started 48 hours before stem-cell reinfusion. Patients were monitored to document the occurrence of neutropenia and fever, incidence and cause of bacterial infection, time to onset and duration of fever, requirement for intravenous antimicrobials, and length of hospital admission.

RESULTS: Sixty-five patients were randomized to receive ciprofloxacin and 65 to receive ciprofloxacin plus rifampin, and from these groups, 62 and 61 were assessable, respectively. The proportion of patients who developed neutropenia and fever was 87% in the group treated with ciprofloxacin and 78% in the group treated with ciprofloxacin and rifampin (P = .25). Although there was a trend toward a reduction in the overall incidence of bacteremia (12 v 4 patients), and Gram-positive bacteremia (8 v 2 patients) with the addition of rifampin, none of these comparisons was statistically significant (P = .05 and P = .09, respectively).

CONCLUSION: The results of this study, which demonstrate that rifampin does not improve ciprofloxacin antibacterial prophylaxis in cancer patients undergoing HDC with PBSCT support but that it does increase the occurrence of undesirable side effects, do not support the routine use of rifampin in this setting.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HIGH-DOSE chemotherapy (HDC) with peripheral-blood stem-cell transplantation (PBSCT) has become a widespread strategy for the treatment of a variety of solid tumors, including breast cancer, germ-cell tumors, ovarian cancer, and lymphoma.¹ Despite the use of hematologic colony-stimulating factors and PBSCT support to accelerate hematologic recovery,^2-5 there is a period of several days of severe neutropenia and mucositis in which there is a high incidence of fever and infection.⁶

The optimal approach to prevent infection in neutropenic patients remains controversial. Early strategies included a protected environment such as laminar air-flow rooms, oral nonabsorbable antibiotics, and selective gastrointestinal decontamination.^7-9 The efficacy of these regimens has been limited by factors such as gastrointestinal intolerance, poor compliance, development of resistance, and superinfection.¹⁰ More recently, oral absorbable antibiotics regimens with fluoroquinolones and trimethoprim/sulfamethoxazole have been found to be effective in the prevention of infection in myelosuppressed patients with cancer.^11-14 A number of features, including their broad-spectrum antibiotic activity, tolerability, and optimal pharmacology when given orally, favor oral fluoroquinolones as the agents of choice for bacterial prophylaxis in patients with anticipated or current neutropenia.¹⁵ A recent meta-analysis of randomized trials of quinolone prophylaxis indicated that, compared with no prophylaxis or trimethoprim/sulfamethoxazole prophylaxis, quinolones significantly reduced the incidence of various infection-related outcomes, including Gram-negative bacterial infections, microbiologically documented infections, and fever.¹⁶

The efficacy of oral quinolones is, however, limited in the prevention of infection-related complications in neutropenic cancer patients. Approximately 70% to 80% of patients in most reported series still developed fever while experiencing neutropenia, despite the prophylactic use of oral quinolones.¹⁷ Furthermore, as demonstrated in the meta-analysis, the use of quinolones did not result in a reduction of Gram-positive infections.¹⁶ In fact, there has been a shift in the relative distribution of the organisms that cause infection in neutropenic cancer patients, and Gram-positive bacteria now account for 70% of all microbiologically documented infections.^18-22 Coagulase-negative staphylococci are the most common isolates, but viridans group streptococci are now increasingly being reported as the cause of bacteremic infection among bone marrow transplantation recipients. Although most patients experience an uncomplicated bacteremia, serious complications, including encephalopathy, respiratory distress syndrome, septic shock, and death, have been reported after infection by this organism in neutropenic cancer patients.^23-25

In recent years, several studies have evaluated whether the addition of antibiotics with activity against Gram-positive bacteria, including roxithromycin, vancomycin, penicillins, and rifampin, to a quinolone-based prophylactic regimen would reduce the incidence of Gram-positive infections and infection-related morbidity in neutropenic cancer patients.^26-32 The combination of ciprofloxacin with rifampin reduced the incidence of fever from 98% to 57% and of Gram-positive bacteremia from 18% to 0% in patients with breast cancer who were undergoing autologous bone marrow transplantation, compared with a historical control group that received no prophylaxis.²⁹ A recent randomized clinical trial conducted in our institutions demonstrated the efficacy of rifampin combined with ciprofloxacin to reduce the occurrence of Gram-positive infections in cancer patients treated with aggressive chemotherapy.³⁰ In addition, similar results also have been observed for the combination of rifampin with ofloxacin.³¹ The incidence of neutropenic fever was equivalent in these two treatment groups and was not effected by the addition of rifampin in any of these studies. These studies, however, were not designed to evaluate the effects of rifampin on the development of fever and were probably underpowered to properly analyze this outcome. Because the presence of febrile neutropenia requires the empirical use of intravenous (IV) antibiotics and hospital admission, irrespective of microbiologic evaluation, this end point is probably more relevant clinically.³³

This multicenter, randomized clinical trial was conducted to evaluate the efficacy of adding rifampin to a ciprofloxacin antibacterial prophylactic regimen to reduce the incidence of fever and neutropenia in adult patients with solid tumors undergoing HDC with PBSCT rescue. Secondarily, this study also analyzed the influence of rifampin prophylaxis on the incidence of bacteremia, Gram-positive bacteremia, and other parameters of infection-related morbidity, such as the time to onset and duration of fever, the requirement and duration of antimicrobial therapy, and the length of hospital admission.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients with a diagnosis of a solid tumor who were hospitalized and scheduled to receive HDC with PBSCT rescue were eligible for the study. Inclusion criteria included the following: (1) age greater than 18 years, (2) no fever or signs or symptoms of infection in the preceding 24 hours, (3) no antibacterial therapy within the preceding 48 hours, (4) no history of allergy to quinolone derivatives or rifampin, and (5) normal renal, cardiac, respiratory, and liver function. All patients provided informed consent and were enrolled onto a protocol approved by the local ethical committee.

Regimen
Patients were randomly assigned by consecutively drawn, sealed envelops to receive ciprofloxacin 500 mg tablets every 8 hours or ciprofloxacin 500 mg tablets every 8 hours plus rifampin 300 mg tablets every 12 hours. Prophylaxis was begun 48 hours before stem-cell reinfusion and was continued until the development of fever (defined below), signs or symptoms of infection, serious adverse effects potentially attributable to the study regimen, or recovery to an absolute neutrophil count (ANC) of greater than 500 cells/µL. Patients with fever were evaluated promptly and were started on empirical broad-spectrum antibiotics as recommended in this setting.³³ Patients received a third-generation cephalosporin (usually ceftazidime) plus amikacin or imipenem monotherapy. A glycopeptide was added if patients remained febrile 48 to 72 hours after the initiation of antibiotics. Amphotericin B was used for documented fungal infection and for fever of undetermined origin that lasted longer than 5 days during the neutropenic period. Antibiotics were maintained until an ANC of greater than 1,000 cells/µL was reached and the patient had remained afebrile for 48 consecutive hours. Documented infections were treated on an individual basis.

Supportive Measures
Patients were cared for in private rooms, each equipped with a bath and toilet. No isolation precautions were used other than universal and careful hand washing. Patients were restricted to low bacterial diets. All subjects received antiviral prophylaxis with acyclovir and were treated with granulocyte colony-stimulating factor to accelerate neutrophil recovery. Magnesium-containing antiacids were prohibited because of interference with ciprofloxacin absorption.

Subject Evaluation
Each patient had a complete medical history and physical examination performed the day of admission and was monitored clinically daily during the hospitalization for fever and signs of infection and for clinical and laboratory manifestations of possible side effects. Vital signs, including temperature, were recorded every 8 hours. Other tests included daily complete blood counts and assessment of serum electrolytes and serum chemistry. A chest x-ray was performed the day of admission. Surveillance cultures were not performed in this trial. Patients with new onset of fever were each evaluated with a complete physical examination, complete blood counts, serum chemistry assessment, and a chest x-ray. Standard methods for the isolation and identification of pathogenic organisms from clinical sites were used. Two blood specimen sets were obtained from the central vein and from a peripheral vein for culture using the BACTEC 6A.7A automated system (Becton Dickinson, Mountain View, CA). Cultures were repeated in patients who remained febrile 48 hours after antibiotics had been started. Urine, stool, and other cultures and studies were performed if clinically indicated. Antibacterial susceptibility was tested by the microdilution system.

Definitions for Efficacy and Toxicity
Patients were considered assessable for toxicity if they took one or more doses of study medication and were considered assessable for efficacy if they took four or more doses of study medication. Patients who did not take study medications because of adverse toxic effects or intolerance were analyzed on an intention-to-treat basis. Adverse effects were attributed to the prophylactic regimen if they occurred during prophylaxis or within 48 hours of the last dose without any other cause to account for it. The principal end point of the study was the prevention of fever and neutropenia, which was defined as an axillary temperature of 38°C taken two times at 4-hour intervals or a single temperature of greater than 38.5°C not related to the administration of blood products concomitant with an ANC of less than 500 cells/µL or between 500 and 1,000 cells/µL that decreased to less than 500 cells/µL within 24 hours. A second febrile episode was considered a temperature elevation, as described above, 48 hours or more after the first episode or fever within the first week after hematologic recovery and antibiotic discontinuation. Infection was defined by the presence of signs/symptoms of inflammation at an anatomic site and was subclassified as microbiologically documented when pathogenic microorganisms were recovered from affected sites and as clinically documented when pathogenic organisms were not recovered from affected sites.^33,34 Bacteremia was defined as the recovery of bacteria from one or more blood cultures. The isolation of coagulase-negative staphylococci, Micrococcus sp., and diphtheroids from a single blood culture was not considered proof of bacteremia unless the isolation of the bacteria occurred in at least two or more blood cultures. Time to onset of fever was calculated from the day of randomization.

Study Design and Statistical Evaluation
This study was an open-label, multicenter, prospective randomized clinical trial. Randomization was stratified by participating institutions. Sample size was calculated to detect a 25% difference in the incidence of neutropenia and fever, from 85% to 63%. With an alpha error of 5% and a statistical power of 80%, 124 subjects (62 per arm) were required. Based on the assumption that approximately 5% of subjects would not be assessable, a total of 130 patients (65 per arm) were enrolled to properly evaluate trial objectives. Differences between groups in qualitative variables were analyzed with Fisher’s exact test. Continuous variables were compared with Student’s t test. Those variables that did not follow a normal distribution were analyzed with the Mann-Whitney nonparametric U test. Censored data such as the time to onset of first fever were analyzed by the long-rank test.

	RESULTS

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General
One hundred thirty consecutive patients, whose characteristics are summarized in Table 1, were enrolled onto the study from two participating institutions (89 from the University Hospital "12 de Octubre" and 40 from the University Hospital de San Pau i Santa Creu). According to the criteria stated above, seven patients (three in the ciprofloxacin arm and four in the ciprofloxacin plus rifampin arm) were nonassessable for efficacy. One patient in each arm underwent an autologous bone marrow transplantation instead of PBCST, and the other five subjects had received IV antibiotics before randomization. One hundred twenty-three patients were finally analyzed in the study; 62 were randomized to receive ciprofloxacin, and 61 were randomized to receive ciprofloxacin plus rifampin. Patients who did not take medication because of oral intolerance were assessed for efficacy in an intention-to-treat analysis. The two groups were comparable with respect to sex, age, underlying malignancy, and chemotherapy regimen (Table 1). The duration of neutropenia, as well as the incidence of severe mucositis and diarrhea, was equivalent in the two groups.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot showing the time between randomization and the onset of the first episode of fever (P = .12, by the long-rank test). Abbreviations: C, ciprofloxacin; C+R, ciprofloxacin + rifampin.

Antibiotic Use
The proportion of patients who required empirical IV antibiotic therapy (87% in the control group and 79% in the combination treatment group) and the mean number of days on antibiotic therapy in these patients (7 and 8 days, respectively) were similar in the two groups. Nine patients in the ciprofloxacin group and 12 in the ciprofloxacin-rifampin group were treated with amphotericin B; none of these patients had documented fungal infections, and amphotericin B was empirically initiated because of the persistence of fever for longer than 5 days. The mean number of days with amphotericin B was similar between the groups (6 and 4, respectively). Data regarding antimicrobial use are summarized in Table 2.

Compliance and Toxicity
The tolerability and compliance with prophylaxis regimens was adequate in both groups with only minor side effects of no clinical significance. However, although toxic effects were modest and tolerable, the frequency of undesirable effects was significantly higher in patients exposed to rifampin (11 patients [18%]) compared with those who were not (0 patients; P = .002). Five patients treated with rifampin developed mild elevation of liver function test in the order of magnitude of two-fold over baseline values that was transient and of no clinical significance. Additionally, six patients complained of gastrointestinal discomfort after a median of 3 days of treatment, which was severe enough to discontinue medication in four cases. None of these four patients developed a bacterial infection potentially attributable to prophylaxis discontinuation.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This multicenter randomized clinical trial was designed to evaluate the efficacy of adding rifampin to reduce the incidence of neutropenia and fever in patients with solid tumors undergoing HDC with PBSCT. The results of this study demonstrate that the addition of rifampin to ciprofloxacin did not result in a relevant reduction in the incidence of neutropenia and fever but had a borderline effect in reducing the incidence of bacteremias and Gram-positive bacteremias. Other parameters of potential clinical relevance, which include the duration and time to onset of fever, the requirement and duration of treatment with IV antimicrobials, and the duration of hospitalization, were basically unmodified with the use of rifampin.

Over the last few years, the most common cause of infection in neutropenic cancer patients has evolved from Gram-negative to Gram-positive bacteria, with Gram-positive cocci being responsible for more than 65% of bacteremic episodes in the early neutropenic period after HDC.^18-22 The reasons for the increased frequency of Gram-positive bacteria are multifactorial and include the higher incidence of severe mucositis resulting from intensive chemotherapy regimens, the use of long-term vascular catheters, and prophylactic administration of quinolone antibiotics.^17,21-24 Coagulase-negative staphylococci represent the most common Gram-positive organisms isolated in this situation. However, bacteria of the viridans streptococci group are being increasingly reported as the cause of bacteremic infections in this population of patients.^18-25 Furthermore, although the clinical course of viridans streptococci bacteremia is usually mild, these organisms have been associated with the development of serious complications, including septic shock, adult respiratory distress syndrome, and death.^18-25 Major risk factors for streptococcal infection in neutropenic patients include treatment with high-dose cytarabine and extensive mucosal damage.²⁵ The increased incidence of Gram-positive bacteremia, as well as the growing concern about the usually benign course of these infections, has resulted in two different therapeutic interventions. Whereas some studies have explored the efficacy of including glycopeptide antibiotics to the initial empirical antibiotic regimen for fever and neutropenia,^36,37 others have investigated the use of prophylactic antibacterial regimens with broad spectrum activity against Gram-positive bacteria.^26-32

Several clinical trials have evaluated the efficacy of adding Gram-positive–targeted antibiotics to a quinolone-based regimen, and their results have been published.^26-32 These studies are heterogeneous with regard to the patient population enrolled, the targeted Gram-positive antibiotics used, and the major objectives. Although all of these studies reported a significant reduction in the incidence of Gram-positive bacteremia in patients treated with Gram-positive active agents, only one of them observed a significant reduction in the incidence of neutropenia and fever.²⁸ The administration of oral penicillin V and roxithromycin plus a quinolone antibiotic has been demonstrated to significantly reduce the incidence of streptococcal bacteremias in neutropenic cancer patients with leukemia or bone marrow transplantation. In addition, penicillin V also reduced the incidence of neutropenia and fever.^26,28 The use of penicillin, however, has resulted in the emergence of penicillin-resistant streptococcal infection.²⁵ Contradictory results have been reported with the use of IV vancomycin to prevent Gram-positive infections in patients undergoing bone marrow transplantation, with one trial demonstrating a significant reduction in the incidence of Gram-positive bacteremia from 30% to 0% when compared with no prophylaxis and another, randomized controlled trial demonstrating no benefits with the inclusion of vancomycin.^27-32 The widespread use of this agent has been associated with the emergence of life-threatening vancomycin-resistant Gram-positive infections.³⁸

Rifampin, an inhibitor of DNA-directed RNA polymerase that has an in vitro antimicrobial spectrum that includes coagulase-negative staphylococci and viridans streptococci, has been extensively evaluated in conjunction with quinolone antibiotics to prevent the development of Gram-positive infections in patients with current or anticipated neutropenia.^29-31 In an initial retrospective study, the combination of rifampin and ciprofloxacin resulted in a significant reduction in the incidence of Gram-positive bacteremia and fever in patients with breast cancer undergoing HDC with autologous bone marrow transplantation.²⁹ Two prospective randomized clinical trials, one of which was performed at our institution, further investigated this hypothesis.^30,31 The administration of rifampin, in conjunction with either ofloxacin or ciprofloxacin, significantly reduced the incidence of Gram-positive bacteremia but did not influence the overall incidence of febrile events in patients with cancer undergoing intensive chemotherapy.

Unlike previous investigations in which the major objective was the reduction in the incidence of Gram-positive bacteremias, the present study focused on the incidence of febrile episodes as the main outcome measurement for several reasons. Although the reduction in the incidence of Gram-positive bacteremia and, particularly, viridans group streptococcus bacteremia is a desirable objective, the relevance of these infections in this patient population is probably not as great as it may be in patients with acute leukemia or treated with bone marrow transplantation who developed prolonged neutropenia and severe mucositis. Patients with solid tumors treated with HDC and PBSCT have a more rapid neutrophil recovery and suffer fewer nonhematologic toxic effects. The mean time with an ANC less than 500 cells/µL is approximately 1 week for studies, including the present one, that enrolled this patient population, which is substantially lower than those reported in studies that accrued patients with acute leukemia and bone marrow transplantation (2 to 3 weeks).^26,28,30,31 In general, these patients are not at high risk for developing viridans group streptococcus bacteremia.²⁵ In fact, only one patient (0.8%) in this study developed a bacteremia with Streptococcus viridans. Additionally, the clinical course of these infections usually is not as devastating as that caused by Gram-negative rods. In contrast, however, the majority of patients with solid tumors treated with HDC and PBSCT developed fever in the early neutropenic period after chemotherapy.³⁰ The occurrence of fever in this period has important clinical consequences because it requires the administration of broad-spectrum IV antibiotics and, in general, admission to the hospital.³³ These factors impose a serious difficulty in the performance of outpatient transplantation procedure.³⁹ Considering that solid tumors, particularly breast cancer, constitute the main indication for HDC procedures,^1,40 the development of fever and neutropenia probably has important economic repercussions. Therefore, the prevention of fever might be considered a more relevant clinical end point in this patient subgroup.

Similar to the results obtained in previous trials, the addition of rifampin did not result in a reduction in the incidence of fever. Furthermore, although there was a clear trend toward a decrease in the number of microbiologic infections, these differences did not reach statistical significance. The reduction in the number of microbiologic infections was counterbalanced by an equivalent increment in the proportion of patients with fever of undetermined origin, which resulted in a similar number of febrile episodes in the two treatment groups. These findings have been reported in other trials of rifampin in combination with quinolones and suggest that some of these episodes of unexplained fever in patients on prophylactic antibiotics might be of noninfectious origin.^30,31 This hypothesis is reinforced by the results of two recent clinical trials in which IV antibiotics were discontinued after brief periods of treatment in patients who received quinolones prophylaxis and who developed neutropenia and fever of unknown origin, which demonstrates the feasibility and safety of this approach.^41,42 Recent studies have evaluated the utility of different serologic markers such as protein C and interleukins to predict the presence of bacteremia in patients with fever and neutropenia before the usual 24 to 48 hours required to obtain the result of blood cultures.^43,44 The development of sensible, specific, and fast serologic markers of bacteremia could potentially make it possible to avoid the requirement for administering IV antibiotics in some patients. There are, however, some other confounding factors and limitations in this study that could influence the observed results. Prophylactic antibiotics were started 48 hours before stem-cell reinfusion, and the majority of patients became febrile by day 6 after prophylaxis was started. Prior studies have documented that the suppression of gut microflora requires more than 1 week of antibiotic administration.³¹ Therefore, it is possible that the introduction of prophylactic antibiotics earlier than the 48 hours timing used in this study could be more efficacious in the prevention of fever. Because the same timing was used in both arms of the study, this factor does not influence the comparison between both regimens but could have affected the overall efficacy of prophylactic antibiotics. The appropriate timing of antibiotics administration should be properly analyzed in future studies. A second bias results from the short duration of neutropenia in this setting, which results, in part, to the routine use of hemapoietic growth factors. The duration of neutropenia is one of the principal risk factors for the occurrence of infectious complications, and it is possible that the potential benefits of prophylaxis in this trial could had been offset by the short duration of neutropenia. In consequence, although the addition of rifampin did not decrease the incidence of fever in these patients, these results are not necessarily applicable to other patient populations with longer durations of severe neutropenia.

One of the potential problems with the use of rifampin may be the emergence of resistance in Gram-positive organisms.⁴⁵ Most Gram-positive organisms in this study were, with the exception of one strain of E faecium, susceptible to rifampin. The emergence of rifampin resistance has been associated with the prolonged use of this agent at relatively low doses and has not been a problem in any of the studies performed so far in which rifampin has been administered at usual doses for short periods of time.^29-31 Preclinical data have indicated that the combination of rifampin with quinolones increases the occurrence of enterococcus infections.⁴⁶ In this regard, it should be noted that one patient in this study developed a bacteremia by E faecium. However, this is the only microorganism of this genus isolated in studies of rifampin in combination with quinolones, and therefore, the clinical relevance of this finding is probably negligible.

In conclusion, the addition of rifampin to ciprofloxacin did not result in either a reduction in the incidence of fever and neutropenia or the improvement in any of the other infection-related end points, such as the time to onset and duration of fever, requirement and duration of antimicrobial treatment, or length of hospital admission. Although the use of rifampin reduced the incidence of bacteremia and, particularly, the incidence of Gram-positive bacteremia, the differences were not statistically significant. In addition, the administration of rifampin resulted in a higher incidence of undesirable, albeit mild, side effects. These results, in conjunction with data from other studies, do not support the routine use of rifampin in this clinical setting.

	ACKNOWLEDGMENTS

 
We are indebted to Dr Amita Patnaik for critical review of the manuscript and for useful suggestions.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted April 30, 1999; accepted January 25, 2000.

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