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Meropenem Versus Ceftazidime in the Treatment of Cancer Patients With Febrile Neutropenia: A Randomized, Double-Blind Trial

From the Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada; the University Hospital St Radboud, Nijmegen, the Netherlands; St Francis Medical Center, Honolulu, HI; and St Joseph Hospital, Orange, CA.

Address reprint requests to Ronald Feld, MD, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9; email ronald.feld{at}uhn.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To compare meropenem, a carbapenem antibiotic, with ceftazidime for the empirical treatment of patients with febrile neutropenia.

PATIENTS AND METHODS: A prospective, double-blind, randomized clinical trial was conducted at medical centers in North America and the Netherlands. A total of 411 cancer patients (196 treated with meropenem and 215 treated with ceftazidime), who had 471 episodes of fever, participated in the trial. For each neutropenic episode, patients were allocated at random to receive intravenous administration of meropenem (1 g every 8 hours) or ceftazidime (2 g every 8 hours). Treatment could be modified at any time. Key end points were clinical and bacteriologic outcomes, eradication of infecting organism, and adverse events.

RESULTS: The rate of successful clinical response at the end of therapy was significantly higher for patients treated with meropenem than for those on ceftazidime for all episodes (54% v 44%, respectively) and for episodes of fever of unknown origin (62% v 46%, respectively), but differences between groups were not statistically significant for clinically defined or microbiologically defined infections. Meropenem was significantly more effective than ceftazidime in severely neutropenic ( 100 cells/µL) patients (55% v 43%, respectively), bone marrow transplant patients (73% v 27%, respectively), and patients given antibiotic prophylaxis before study entry (71% v 52%, respectively). Common adverse effects of meropenem and ceftazidime therapy were rash, diarrhea, and nausea and vomiting.

CONCLUSION: Monotherapy with meropenem represents a suitable choice for initial empirical antibiotic therapy for febrile episodes in neutropenic cancer patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
INFECTIOUS COMPLICATIONS are the leading cause of death among neutropenic cancer patients, but early initiation of empirical antibiotic therapy can reduce associated morbidity and mortality.^1-3 Although combination antibiotic regimens have been widely used as initial therapy for febrile neutropenic cancer patients, controlled trials have demonstrated no striking differences between multidrug regimens and single agents,^4-9 and monotherapy is considered a standard of treatment.¹⁰

Ceftazidime, a third-generation cephalosporin, has been thoroughly studied as a monotherapy^11-13 or combination therapy¹⁴ for febrile neutropenia. Although its efficacy is well established, ceftazidime, like most cephalosporin antibiotics, has only limited activity against Gram-positive bacteria, and resistance of Gram-negative organisms to ceftazidime is of concern. The carbapenem class of beta-lactam antibiotics, which offers a broad spectrum of activity against both Gram-positive and Gram-negative organisms (including anaerobes) and possesses wide bactericidal activity, represents a promising alternative option for monotherapy. Imipenem and cilastatin, the first commercially available carbapenem, is as effective as ceftazidime¹⁵ and combination regimens,^16-20 but when administered in a daily dose of 4 g, it is associated with a higher incidence of nausea and vomiting ^15,17,18 and seizures,^18,19 relative to comparator drugs. A 2-g/d dose of imipenem and cilastatin has better tolerability than the higher dose and has not been associated with a higher incidence of seizures.¹⁸

Meropenem is a carbapenem antibiotic with a spectrum of activity similar to that of imipenem and cilastatin. Unlike imipenem and cilastatin, meropenem does not require coadministration with an enzyme inhibitor,²⁰ and its overall toxicity profile compares favorably with that of imipenem and cilastatin. Meropenem monotherapy in patients with febrile neutropenia has been evaluated in five published trials and has been shown to be as well tolerated and as effective as ceftazidime,^21,22 imipenem and cilastatin,²³ or ceftazidime plus amikacin.^24,25 None of these trials, however, used a double-blind design to minimize bias. We undertook a prospective, double-blind, multicenter trial to compare the efficacy and safety of meropenem and ceftazidime when used as monotherapy for the empirical treatment of febrile neutropenia in patients with cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Population
Hospitalized patients aged 18 years or older with malignancies, fever, and neutropenia and with known or suspected bacterial infections were eligible for inclusion in the trial. Fever was defined as either a single oral temperature exceeding 38.3°C or two oral temperatures exceeding 38°C within a 12-hour period. Neutropenia was defined as an absolute neutrophil count of less than 500 cells/µL or 500 to 1,000 cells/µL at the time a fever developed, with the expectation that the count would decrease to less than 500 cells/µL within 24 to 48 hours of trial entry. In the absence of an absolute neutrophil count, neutropenia was defined as a total WBC count of 500 cells/µL. As is common in such trials, 16 patients could be enrolled for multiple separate episodes of fever and neutropenia, provided a previous episode had resolved, treatment for the previous episode had been completed at least 7 days before enrollment, no prior withdrawal because of an adverse event had occurred, and causative organisms previously isolated were sensitive to treatment with meropenem and ceftazidime.

Patients were excluded if they had rapidly progressing underlying disease; a history of sensitivity to penicillin, cephalosporin, or carbapenem antibiotics; marked hepatic disease, infectious hepatitis, or positive human immunodeficiency virus status; marked renal function impairment; CNS disease, including a history of seizures or any condition that increased the risk of seizures; chronic lymphocytic leukemia; cystic fibrosis; if they were using immunomodulators; or if they had used any investigational drug other than meropenem and ceftazidime within 30 days of the start of the trial. Women who were pregnant or lactating were excluded from the trial. Patients were also excluded if they had received another antibiotic within 72 hours of the start of the trial, except when isolated pathogens were resistant to earlier treatment, the infection was uncontrolled, or the antibiotic was used for bowel decontamination. Prophylactic use of antiviral or antifungal medication was permitted provided patients were receiving such medication at the time of trial entry.

Study Design
The trial was conducted at 13 sites in the United States and Canada and one in the Netherlands during the period between September 1991 and January 1993. An institutional review board at each site approved the trial protocol, and each patient or his or her legal guardian provided written informed consent.

Eligible patients completed a medical history and underwent a physical examination. Clinical laboratory tests, including hematologic and serum chemistry tests as well as urinalysis, were performed before initiation of antibiotic therapy. Women underwent a serum human chorionic gonadotropin test for pregnancy status. Patients were assessed for clinical signs and symptoms as well as bacteriologic evidence of infection. Two blood cultures and cultures from suspected or proven sites of infection were required no more than 3 days before initiation of antibiotic therapy. However, trial medication could be administered before the results of bacteriologic cultures were known. Cultures from surgical drains or intubation tubes were obtained only when clinically indicated.

After completing a pretherapy evaluation, patients were allocated at random for each neutropenic episode to receive an intravenous infusion of either meropenem (Merrem; Zeneca Pharmaceuticals, Wilmington, DE) 1 g every 8 hours or ceftazidime (Fortaz; Glaxo-Wellcome, Inc, Research Triangle Park, NC) 2 g every 8 hours; the recommended treatment duration for both drugs was 7 days. Blinded drug was distributed based on a schedule that provided a stratified, balanced, block random assignment within each center; stratification was by the presence or absence of prophylactic treatment with antiviral or antifungal medication. As patients were enrolled for specific neutropenic episodes, they were assigned the next available number and associated randomized treatment.

Once assigned to receive meropenem or ceftazidime for a specific episode, patients continued to receive that regimen until the febrile episode resolved or treatment was discontinued or modified. During the trial period, blood cultures that tested positive initially were repeated at 72 hours and daily thereafter until fever and neutropenia resolved. Laboratory tests were repeated on day 3 and at least weekly thereafter if therapy was continued beyond 7 days. It was recommended that laboratory tests with clinically significant results be repeated at least weekly until values normalized or returned to pretreatment levels.

Patients also underwent a follow-up clinical assessment approximately 7 days after completing therapy. Repeat bacteriologic cultures, laboratory tests, and other diagnostic procedures were performed as appropriate. The antimicrobial susceptibility of pathogens to meropenem and ceftazidime was determined by disk diffusion or broth microdilution method, according to National Committee for Clinical Laboratory Standards.^26,27

Modification or Discontinuation of Initial Therapy
Initial therapy could be modified at any time at an investigator’s discretion. No additional antibiotic therapy was permitted with administration of meropenem or ceftazidime. When any new antibiotic was added, patient episodes were classified as failures. Antifungal or antiviral medication could be added to initial therapy for a confirmed fungal or viral infection, and when this occurred after 72 hours of initial therapy, it was considered a treatment modification. However, when any new antifungal or antiviral therapy was added before 72 hours of initial therapy had been completed, patient episodes were classified as failures. Patients who developed diarrhea during the course of therapy and had a stool sample that tested positive for Clostridium difficile toxins were permitted to remain in the trial and receive treatment with oral vancomycin.

Treatment with either drug could be discontinued because of an intolerable side effect, disease exacerbation, or when patients elected to withdraw from therapy. Patients who withdrew before completing therapy underwent a clinical evaluation, and samples from appropriate sites were cultured.

Classification of Infections
When there were clinical signs and symptoms of infection but no pathogen was isolated from the infection site, the infection was considered clinically defined. When a pathogen was isolated from a blood sample, an infection site, or both, the infection was considered microbiologically defined. Bacteremia was diagnosed when a positive blood culture was accompanied by fever or hypothermia (ie, temperature 37°C), together with clinical signs such as tachycardia and hypotension unrelated to administration of drug therapy or blood transfusions. Fever of unknown origin was diagnosed when fever was the only clinical sign of infection.

A minimum of 3 consecutive days with a maximum daily temperature 38°C were required for defervescence. Patients were considered to have a new fever after defervescence if their maximum daily temperature was 38°C.

Efficacy Evaluation
Clinical response was assessed at the end of treatment and the end of the 7-day follow-up period. Success was defined as cure, cure with modification (development of new fever after initial defervescence, requiring a change in antimicrobial agent or addition of antifungal or antiviral treatment), or improved. Failure was defined as unchanged, worsening, or relapse.

Bacteriologic response for all infections except those of the urinary tract was determined by comparing pretreatment cultures with cultures obtained at the end of treatment and follow-up. Success was defined as either eradication (pretreatment pathogens were eradicated at the end of treatment) or presumed eradication (no suitable material was available for culture, but the patient had a satisfactory clinical response). Failure was defined as persistence (elimination of some or none of the pretreatment pathogens), presumed failure (no suitable material was available for culture, but the patient had persistence or worsening of clinical signs of infection), or superinfection (presence of one or more new pathogens during treatment or follow-up associated with infection requiring additional antibiotic therapy or surgical intervention).

Bacteriologic response for urinary tract infections was assessed after 72 hours of treatment and 7 days after the end of therapy. Response to therapy was successful when a urine culture for the initial pathogen was negative after 72 hours of treatment and at the 7-day follow-up assessment. All other outcomes after 72 hours and at follow-up represented unsatisfactory bacteriologic response.

Deaths occurring within 72 hours of therapy were considered treatment failures for both clinical and bacteriologic response. Deaths occurring after 72 hours were considered treatment failures when the infection either contributed to or caused the patient’s death.

Safety Evaluation
The safety of trial medications was evaluated by monitoring patients for the development of adverse events, significant changes in laboratory values, and local intolerance to intravenous drug infusions.

Statistical Methods
The primary analysis was a comparison of response rates for the meropenem and ceftazidime groups. The trial was designed to have 80% power with a two-sided significance level to detect a difference between treatment groups in response rates (70% and 52.2%), assuming 130 assessable episodes per treatment group. Efficacy was analyzed for the modified intent-to-treat population (all randomized patients with documentation of fever and neutropenia who received trial medication). Subgroup analyses were performed for patients who had received a bone marrow transplant and patients who had a neutrophil count of 100 cells/µL at the time of trial entry. In addition, a posthoc analysis was performed to determine whether the presence or absence of antibiotic prophylaxis at the time of trial entry affected outcome for clinical response. Safety analysis was performed for the intent-to-treat population (all randomized patients who received trial medication).

All analyses were performed using a two-tailed Student’s t test with an alpha level of 0.05. The outcomes for clinical and bacteriologic response were analyzed using logistic regression analysis. The model used included treatment, the initial primary infection classification, and the presence or absence of prophylactic antifungal or antiviral therapy. Subgroup analyses by primary infection classification and presence or absence of antibiotic prophylaxis were performed using the Cochran-Mantel-Haenszel test. In addition, time-to-event analyses were performed for duration of monotherapy, defervescence, and resolution of neutropenia using survival analysis methods. The overall treatment effect was determined by Cox proportional hazards regression analysis, which included terms for initial primary infection classification and the presence or absence of prophylactic antiviral or antifungal treatment.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Pretreatment and Demographic Characteristics
Four hundred eleven patients with neutropenia (196 scheduled to receive meropenem and 215 scheduled to receive ceftazidime) were enrolled in the trial and had 471 episodes of fever within the trial period (Fig 1). The treatment groups formed by randomization of patient episodes were well-balanced with respect to sex, race, age, background therapy, underlying cancer, other risk factors, defining infection, and duration of neutropenia before trial entry (Table 1).

View larger version (23K): [in this window] [in a new window]   Fig 1. Flowchart of patient episodes.

Clinical Response
The rate of successful clinical response was significantly higher for meropenem than for ceftazidime for all episodes (Table 2) and for episodes of fever of unknown origin (Table 3). The difference between groups was attributable to a greater number of completely cured episodes for meropenem than for ceftazidime for all episodes (35% v 27%, respectively) and episodes of fever of unknown origin (41% v 30%, respectively). The differences between groups for both clinically and microbiologically defined infections were not statistically significant.

Analysis of clinical response according to whether or not patients received antibiotic prophylaxis revealed a significantly higher rate of successful clinical response in the group that received prophylaxis compared with the group that received no prophylaxis (56% v 36%, respectively; P < .001). When clinical response was assessed by treatment for these two groups, the results revealed a significantly higher response for meropenem compared with ceftazidime among patients who received prophylaxis but no difference between groups among those who received no prophylaxis (Table 3).

End of Follow-Up
Consistent with results at the end of follow-up, the rate of successful clinical response was higher for meropenem for all episodes, but the differences were not statistically significant. Meropenem achieved a greater percentage of successful clinical response in clinically defined infections, whereas ceftazidime achieved a greater percentage in microbiologically defined infections. Consistent with the results at the end of therapy, the rate of successful clinical response for fever of unknown origin was significantly higher for meropenem than for ceftazidime (56% v 43%, respectively) (P = .041).

The percentage of successful clinical response was again higher for meropenem than for ceftazidime in severely neutropenic patients, but this difference was not statistically significant (48% v 41%, respectively; P = .052). Similar to the results at the end of therapy, the percentage of successful clinical response was significantly higher for meropenem than for ceftazidime in patients who had received a bone marrow transplant (65% v 28%, respectively; P = .001).

Bacteriologic Response
At the end of therapy, the rate of successful bacteriologic response in microbiologically defined infections was higher for ceftazidime than for meropenem, but the difference between groups was not statistically significant (51% v 45%, respectively). Results between groups at the end of follow-up were similar to those at the end of therapy, with no statistically significant difference between groups.

The overall bacteriologic eradication rate was 93% (40 of 43 organisms) for meropenem and 94% (50 of 53 organisms) for ceftazidime. All isolates from patients were susceptible to both meropenem and ceftazidime. Table 4 lists the eradication rate by organism for patients with bacteremia, which accounted for 92 of the 96 total isolates. For bacteremia, meropenem eradicated 94% of Gram-positive organisms and 96% of Gram-negative organisms, whereas ceftazidime eradicated 92% of Gram-positive and 96% of Gram-negative organisms. Three organisms were associated with urinary tract infections; meropenem eradicated one Pseudomonas aeruginosa isolate but failed to eradicate one Escherichia coli isolate, whereas ceftazidime eradicated one Klebsiella pneumoniae isolate. In 11 episodes (six treated with meropenem and five treated with ceftazidime), more than one pathogen was identified before treatment.

Duration of Therapy, Fever, and Neutropenia
Duration of therapy, fever, and neutropenia were calculated as mean values with SEs as well as median values and interquartile ranges. Because these data were not normally distributed, the results are appropriately described using the median and interquartile range. The difference between meropenem and ceftazidime was not statistically significant for duration of therapy, fever, or neutropenia.

The median duration of therapy was 8 days (interquartile range, 5 to 12 days) for meropenem and 7 days (interquartile range, 5 to 11 days) for ceftazidime. The median number of days during which patients received no modification of initial monotherapy was 11 days (interquartile range, 4 to 33 days) for meropenem and 7 days (interquartile range, 4 to 40 days) for ceftazidime.

The median time to defervescence was 7 days (interquartile range, 4 to 15 days) for meropenem and 7 days (interquartile range, 3 to 18 days) for ceftazidime. The median time to resolution of neutropenia was 15 days (range, 11 to 21 days) for meropenem and 13 days (range, 9 to 20 days) for ceftazidime.

Modification of Initial Therapy
No modification of initial therapy was needed for 40% of episodes in the meropenem group and 32% of episodes in the ceftazidime group (Table 5). During the first 72 hours of therapy, the initial therapy was most often modified in the absence of any evidence of clinical deterioration. During the period after 72 hours of treatment and before the end of therapy, the most common reason for treatment modification was the development of a new bacteremia, fever, or infection focus; whereas during the follow-up period, the most common reason was treatment failure, which included relapse. During the period from the start of therapy to the end of follow-up, treatment was modified in the absence of evidence of clinical deterioration in 33 (27%) of 124 episodes for meropenem and 44 (32%) of 138 episodes for ceftazidime.

Safety. The most common treatment-related adverse events (ie, those judged to be possibly, probably, or definitely related to therapy) were rash (5.3% for meropenem v 5.1% for ceftazidime), diarrhea (5.3% v 4.3%), nausea and vomiting (6.2% v 1.3%), headache (1.3% v 0.4%), abdominal pain (0.4% v 1.3%), and dizziness (1.3% v 0). Two patients (one in each group) reported seizures during either treatment or follow-up. Neither event was considered related to drug therapy.

Drug-related adverse events resulted in the withdrawal of 19 patients (12 in the meropenem group and seven in the ceftazidime group). The most common reason for withdrawal was rash (six meropenem patients and four ceftazidime patients). Other reasons for withdrawal among meropenem-treated patients included rash and petechia, pruritus, diarrhea, recurrent fever and possible drug fever, and abnormal clinical laboratory test result (one patient each), and vasodilatation, petechia, dyspnea, and edema (one patient). Other reasons for withdrawal among ceftazidime-treated patients included rash and possible drug fever, diarrhea and abdominal pain, and nausea and vomiting (one patient each).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The finding from this double-blind trial that meropenem and ceftazidime are effective therapies for febrile neutropenic patients is consistent with results from open-label trials,^21,22 but this investigation is the first to demonstrate a significant difference for meropenem over ceftazidime for one or more outcome measures. We cannot account for the higher rate of successful clinical response with meropenem in episodes of fever of unknown origin. It is well established that the usefulness of ceftazidime in febrile neutropenic patients may be limited in infections caused by Gram-positive organisms; hence, one possible explanation to account for the differences between treatments is that the majority of episodes of fever of unknown origin were infectious fevers attributable to undetected Gram-positive organisms that responded better to meropenem therapy than to ceftazidime therapy. However, the finding that the two drugs had very similar eradication rates in Gram-positive organisms in bacteremia patients does not support this explanation. An alternative explanation to account for the difference between meropenem and ceftazidime in these episodes is the presence of undetected anaerobic pathogens, although such pathogens are rarely isolated from febrile neutropenic patients.

The sample size of our trial was sufficient to perform subgroup analyses to compare the efficacy of meropenem and ceftazidime. The significantly better response to meropenem than to ceftazidime in the subgroup of severely neutropenic ( 100/µL) patients at the time of trial entry and the subgroup of patients who had received a bone marrow transplant suggests that meropenem may be a useful therapy for these high-risk groups. The higher response rate for meropenem than for ceftazidime may possibly reflect a broader spectrum of coverage against undetected unusual pathogens or resistant pathogens, but further investigation is required. The higher rate of successful response in the group that received antibiotic prophylaxis compared with the group that received no prophylaxis is not surprising because patients who are given antibiotic prophylaxis generally have fewer Gram-negative infections than those who receive no prophylaxis. The superior response rate in the meropenem group relative to the ceftazidime group among patients who received prophylaxis may reflect the inherent selection for Gram-positive and anaerobic bacteria with greater resistance to ceftazidime.

Because definitions of response are not consistent among published trials, it is difficult to directly compare results from this trial with other trials testing the value of empirical antibiotic therapy for febrile neutropenia. Moreover, outcome in neutropenia trials may be affected by the response definitions used when the major end point compares the response rate of two or more initial antibiotic regimens.²⁸ Although a single response definition for clinical trials of empirical antibiotic therapy for febrile neutropenia has recently been proposed,²⁹ no consensus was available on the various definitions at the time our trial commenced, and for that reason, the response definitions used in our trial differ from those used in other controlled trials. By using a double-blind trial design, we reduced the likelihood that inappropriate treatment modifications by the investigators would bias the results.³⁰ Hence, the differences between treatments seen in this trial likely reflect a true difference, although the findings require confirmation.

The types of pathogens isolated from patients in our trial were consistent with those commonly associated with infection in neutropenic patients,⁸ and meropenem and ceftazidime had similar overall rates of eradication. Gram-positive organisms accounted for 55 isolates and Gram-negative organisms for 41 isolates, underscoring the need to use antibiotics that provide broad coverage. The eradication rate for Gram-positive organisms was similar for meropenem and ceftazidime; however, the low number of isolates prevented us from drawing any definitive conclusions. Meropenem does have greater in vitro activity against Gram-positive organisms, including Streptococcus faecalis, and most clinically important anaerobes (eg, Bacteroides fragilis and Clostridium sp.) when compared with ceftazidime. Therefore, it may offer better coverage when used in patients with infections caused by these organisms. The final selection of empirical antibiotic regimen for use at a treatment center should be based on local antimicrobial resistance patterns.

Meropenem and ceftazidime were both well tolerated, with the most common adverse events being rash, diarrhea, and nausea and vomiting. A higher incidence of treatment-related nausea and vomiting was evident among meropenem-treated patients, but these events were mild or moderate in intensity and did not lead to withdrawal from therapy. Nausea and vomiting are established side effects of therapy with carbapenem antibiotics, but their incidence seems to be lower with meropenem than with imipenem and cilastatin. Unlike patients given high-dose imipenem and cilastatin therapy in one trial,¹⁵ those in our trial did not develop severe nausea and vomiting that required withdrawal from therapy. Other trials have shown a higher incidence of nausea with imipenem and cilastatin than with ceftazidime or cefoperazone plus piperacillin¹⁸ or with amikacin plus piperacillin¹⁷ when given at therapeutic dosages. Although there were no treatment-related seizures reported among patients in this trial, we excluded from participation any patient who had a history of seizures or any condition that increased the risk of seizure.

In conclusion, our results demonstrate that meropenem and ceftazidime are effective and well tolerated when used as initial empirical treatment for febrile neutropenic cancer patients. Meropenem may be more effective than ceftazidime, as evidenced by a significantly better response in two outcome measures. Although meropenem was also more effective than ceftazidime in two subgroups of high-risk patients, the results must be interpreted with caution in the absence of data from a confirmatory trial in the specific subsets of patients.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators participated in this trial: Steven Berman, MD, St Francis Medical Center, Honolulu, HI; James Hathorne, MD, Duke University Medical Center, Durham, NC; Winston Ho, MD, St Joseph Hospital, Orange; James Ito Jr, MD, City of Hope Medical Center, Duarte, CA; Stephen P. Kanner, MD, Hollywood Medical Center, Hollywood; Reuben Ramphal, MD, David Oblon, MD, and Ward D. Noyes, MD, Shands Hospital at the Gainesville Health Center, The University of Florida, Gainesville, FL; George Pipoly, MD, The Toledo Hospital, Toledo, OH; Robert Swenson, MD, Fox Chase Cancer Center, Philadelphia, PA; Ben DePauw, the University Hospital St Radboud, Nijmegen, the Netherlands; Gary E. Garber, MD, Ottawa General Hospital; Raphael Saginur, MD, Ottawa Civic Hospital, Ottawa; Armand Keating, MD, Princess Margaret Hospital, University of Toronto, Toronto; and Lionel Mandell, MD, and Coleman Rotstein, MD, Henderson General Hospital, Hamilton, Ontario, Canada.

	ACKNOWLEDGMENTS

 
Supported by a grant from AstraZeneca Pharmaceuticals, Wilmington, DE.

We thank Margaret Minkwitz, PhD, for statistical analysis and Gary Dorrell, MS, ELS, and Kendall Wills Sterling, ELS, for editorial assistance. AstraZeneca Pharmaceuticals (Wilmington, DE) supplied investigators with meropenem laboratory standard powder and sensitivity disks (10 µg).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted March 23, 2000; accepted June 16, 2000.

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