Cefepime versus Ceftriaxone for Empiric Treatment of Hospitalized Patients with Community-Acquired Pneumonia

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1998, p Vol. 42, No /98/$ Copyright 1998, American Society for Microbiology Cefepime versus Ceftriaxone for Empiric Treatment of Hospitalized Patients with Community-Acquired Pneumonia M. ZERVOS, 1 * M. NELSON, 2 AND THE CEFEPIME STUDY GROUP 1,2 Infectious Diseases Division, Wayne State University, William Beaumont Hospital, Royal Oak, Michigan, 1 and Medical Services, Veterans Administration Medical Center, Kansas City, Missouri 2 Received 21 April 1997/Returned for modification 24 June 1997/Accepted 10 January 1998 Effective empiric treatment of pneumonia requires antibiotic coverage against gram-negative and grampositive pathogens, including drug-resistant isolates. We compared the safety and efficacy of intravenous (i.v.) cefepime (2 g administered every 12 h) to those of i.v. ceftriaxone (1 g administered every 12 h) for the empiric treatment of hospitalized patients with community-acquired pneumonia. Of the 115 patients randomized to the study, 86 (cefepime recipients, n 40; ceftriaxone recipients, n 46) were evaluated for clinical efficacy (clinically evaluated patients). Favorable clinical outcomes (cure or improvement) were comparable among clinically evaluated patients in the cefepime and ceftriaxone treatment arms (95.0 versus 97.8%, respectively; 95% confidence interval for treatment difference [data for ceftriaxone group minus data for cefepime group], 5.1 to 10.8%). The most common bacteria isolated from patients in both treatment groups were Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. In clinically evaluated patients with a microbiologic response, all (100%) of the 32 pathogens from cefepime-treated patients and 97.4% (38 of 39) of the pathogens from ceftriaxone-treated patients were eradicated (documented or presumed eradication). The one persistent infection in the ceftriaxone group was caused by Pseudomonas fluorescens. Both treatments were well tolerated. Our data thus suggest that cefepime and ceftriaxone have comparable safety and efficacy for the treatment of pneumonia in hospitalized patients. Pneumonia is responsible for more than 500,000 hospital admissions annually and continues to be a major cause of morbidity and mortality in the United States (4). This disease is the most frequent infectious cause of death and the sixth most frequent cause of all deaths in the United States (11, 13). The diagnosis of pneumonia can be difficult to establish, particularly in patients with other comorbid medical conditions, such as chronic lung disease, malignancy, congestive heart failure, or adult respiratory distress syndrome (17). Determination of the causative pathogen can also be difficult. Although advances in microbiologic techniques have aided in identifying the pathogens responsible for pneumonia, accurate bacteriologic diagnosis remains elusive for many patients. The treatment of pneumonia is therefore generally empiric and is based on the knowledge of the most prevalent pathogens, the clinical setting, and drug resistance patterns. Pathogens commonly associated with community-acquired pneumonia include Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, but gram-negative bacteria may also be involved (9, 10). Gram-negative bacteria play a particularly important role in patients who are elderly, who are hospitalized, or who have a serious comorbid illness (5, 6). Cefepime, a fourth-generation cephalosporin recently introduced in the United States, has an extended spectrum of activity that encompasses both gram-positive organisms, such as S. aureus and S. pneumoniae, and gram-negative pathogens, including Pseudomonas aeruginosa, Enterobacter spp., and other members of the family Enterobacteriaceae that are becoming * Corresponding author. Mailing address: William Beaumont Hospital, 3601 West 13 Mile Rd., Royal Oak, MI Phone: (248) Fax: (248) mzervos@beaumont.edu. The Cefepime Study Group includes the following investigators, who enrolled patients in the study: J. Bernstein, D. Kernodle, R. McCabe, N. Memon, R. Player, A. Quartin, C. VanHook, and S. Willsie. increasingly resistant to expanded-spectrum cephalosporins (6, 7, 19, 20). In this study, we therefore compared the empiric use of cefepime to that of ceftriaxone, an expanded-spectrum cephalosporin, for the treatment of hospitalized patients with pneumonia. MATERIALS AND METHODS Study design. This study was an open-label, randomized, comparative, multicenter study involving 115 adult patients with community-acquired pneumonia who were recruited from 10 U.S. centers over a 12-month period. Patients were randomized (1:1) to receive intravenous treatment with either cefepime (2 g every 12 h) or ceftriaxone (1 g every 12 h) for 5 to 10 days (maximum duration, 14 days). The intravenous administration of both drugs occurred over a period of 30 min. The protocol allowed the study drugs to be administered intramuscularly (i.m.) to continue or complete a course of treatment. Concomitant treatment with erythromycin or metronidazole was allowed when infection with Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, or a cephalosporin-resistant anaerobic organism was suspected. Signed informed consent was obtained from all patients or a legally authorized representative. Institutional review board approval was received from all institutions that enrolled patients in the study. Patient eligibility. Hospitalized patients 18 years of age and older with clinical signs and symptoms of pneumonia were eligible for enrollment. Evidence of community-acquired pneumonia was defined by documentation of at least two of three of the following groups of signs and symptoms (i) fever (temperature greater than 38 C) or hypothermia (temperature less than 36 C); (ii) purulent sputum ( 25 polymorphonuclear leukocytes and 10 squamous cells/low-power field), leukocytosis (leukocyte count, 10,000/mm 3 ), worsening arterial oxygen gradients in relation to baseline measurements, or newly developed hypoxia; or (iii) evidence of pulmonary involvement probably due to the presence of bacteria susceptible to cefepime and ceftriaxone (radiologic findings consistent with the diagnosis of aspiration pneumonia, lobar pneumonia, or diffuse unilateral or bilateral pneumonia and/or signs of pulmonary consolidation or pneumonia on physical examination). At least one prestudy sputum or lower respiratory tract specimen was to be obtained for testing of the in vitro susceptibility of the infecting organism(s) to the study drugs. Exclusion criteria for this study included previous treatment with cefepime or ceftriaxone for this episode of pneumonia, a history of hypersensitivity to a cephalosporin or penicillin antibiotic, pregnancy or breast-feeding, creatinine clearance of 11 ml/min, anticipated treatment with other systemic bacterial drugs (with the exception of erythromycin or metronidazole), thrombocytopenia or granulocytopenia expected to last more than 7 days, resistance of the primary 729

2 730 ZERVOS ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Demographic characteristics of randomized patients Characteristic (n 59) (n 56) Sex (no. [%]) a Male 36 (61.0) 43 (76.8) Female 23 (39.0) 13 (23.2) Race (no. [%]) Black 21 (35.6) 21 (37.5) Hispanic 0 2 (3.6) Asian 1 (1.7) 0 White 37 (62.7) 32 (57.1) Other 0 1 (1.8) Mean age (yr) Mean wt (kg) b a P b Data were available for 49 cefepime-treated patients and 47 ceftriaxonetreated patients. infecting organism to the assigned study drug, the presence of pulmonary secretions that were known to be culture negative before therapy was initiated, and the presence of a medically significant condition that could affect study outcome or limit survival during therapy and follow-up (i.e., cystic fibrosis; pneumonia distal to obstructive carcinoma; empyema; positive human immunodeficiency virus status; documented Legionella, Mycoplasma, or Chlamydia pneumonitis; severe cardiac disease characterized by pulmonary edema or unstable congestive heart failure; serious hepatic disease; and concurrent meningitis, osteomyelitis, or infective endocarditis). Study procedures. Upon entering the study, each patient s medical history was recorded and a physical examination, chest radiography, sputum and blood culture analysis, and antibiotic sensitivity testing were performed. Clinical laboratory studies included hematology and serum chemistry analyses and urinalysis. During therapy, clinical evaluations were performed daily during the first week and every 2 to 3 days thereafter to evaluate the efficacy and safety of the study drugs. Blood samples were recultured at least every 3 days until they were negative and at the end of therapy. Clinical laboratory studies were repeated twice weekly during the first week, weekly thereafter during therapy, and within 72 h of the discontinuation of therapy. A posttreatment evaluation, performed within 72 h of the completion of therapy, included a clinical evaluation to determine the presence or absence of signs and symptoms of pneumonia or adverse events, culture analysis of a sputum or lower respiratory tract sample, and chest radiography. Respiratory secretions were cultured for routine respiratory pathogens by standard procedures. Susceptibility to cefepime and ceftriaxone was determined at each study site by either disk diffusion or MIC methods by using National Committee for Clinical Laboratory Standard guidelines. Evaluation of efficacy. Patients were considered clinically evaluable if they met all pretherapy, on-therapy, and posttherapy criteria and received study drug for at least 5 days. The clinical response of each patient was categorized as (i) cure (complete resolution of all signs and symptoms of pneumonia and improvement or lack of progression of all positive findings on chest radiography), (ii) improvement (improvement of one or more signs and symptoms of pneumonia without a complete resolution but a lack of progression of radiographic findings), or (iii) failure (failure to resolve signs and symptoms of pneumonia or progression of infection on chest radiography). The microbiologic response to treatment was defined as follows: (i) eradication (elimination of the original pathogen[s] from subsequent cultures), (ii) presumptive eradication (presumed elimination of the original pathogen[s] as evidenced by the absence of appropriate material for culture at the original site of infection), (iii) persistence (continued presence of the pathogen[s] from the original site of infection during or upon completion of therapy with or without evidence of infection), or (iv) relapse (eradication and then reisolation of the initial pathogen[s]). Pathogens other than the original organism that were isolated from cultures of sputum specimens during therapy or within 3 days of the completion of therapy were judged to be superinfection or colonization. Statistical analysis. Statistical analyses were performed to compare demographic and baseline medical characteristics, efficacy, and safety. In determining the homogeneity of the two treatment groups, including demographic and baseline medical characteristics, categorical variables were analyzed by either the Fisher exact test or the Cochran-Mantel-Haenszel test, and quantitative variables were analyzed by two-way analysis of variance. Clinical and microbiologic response rates were compared by the Cochran-Mantel-Haenszel test, and the rates of incidence of adverse events were compared by the Fisher exact test. RESULTS Patient characteristics. A total of 115 patients with pneumonia were randomized to the study, 59 to the cefepime group and 56 to the ceftriaxone group. The demographic characteristics of these patients are presented in Table 1. There were no significant differences in the races, ages, heights, or weights of the patients entering the study. Both groups had more males than females. Compared to the cefepime group, the ceftriaxone group had significantly more males (36 versus 43; P 0.046). The characteristics of the baseline medical histories that were significantly different between the treatment groups included prevalence of eye, ear, nose, or throat disease (cefepime group, n 16; ceftriaxone group, n 25; P 0.026); the infection under study as the diagnosis for hospitalization (cefepime group, n 50; ceftriaxone group, n 55; P 0.009); and recent trauma (cefepime group, n 4; ceftriaxone group, n 0; P 0.048). Histories of bronchopulmonary disease and tobacco use were each present in approximately 60% of the patients in both groups. The presenting clinical signs and symptoms of pneumonia at study entry were similar for each treatment group (Table 2). Lobar pneumonia was the most common diagnosis. More patients in the cefepime group than in the ceftriaxone group had a right lung infection (47 versus 34; P 0.046); the cefepime group also had more mild infections (11 versus 6; P 0.025). No other significant differences between the study groups were noted. Of the 115 patients who entered the study, 21 (cefepime group, n 12; ceftriaxone group, n 9) discontinued treatment before completing the study. The reasons for discontinuation were protocol violations, including no isolation of a pathogen (cefepime group, n 5; ceftriaxone group, n 2), adverse experience (cefepime group, n 3; ceftriaxone group, n 1); patient s request (cefepime group, n 2; ceftriaxone group, n 2), loss to follow-up or unevaluable (cefepime TABLE 2. Pneumonia characteristics of randomized patients at study entry a Characteristic Cefepime (n 59) Ceftriaxone (n 56) Diagnosis Lobar pneumonia 43 (72.9) 44 (78.6) Bronchopneumonia 15 (25.4) 12 (21.4) Interstitial infiltrate 1 (1.7) 0 Site b Right lung 47 (79.7) 34 (60.7) Left lung 12 (20.3) 22 (39.3) Severity b Mild 11 (18.6) 6 (10.7) Moderate 48 (81.4) 46 (82.1) Severe 0 4 (7.1) Chronicity Acute 58 (98.3) 56 (100) Other 1 (1.7) 0 Classification Single lung lobe 40 (67.8) 38 (67.9) Multiple lung lobe 6 (10.2) 5 (8.9) Both lungs 13 (22.0) 13 (23.2) a The mean number of days of infection before study entry were 4.5 and 5.7 for the cefepime and ceftriaxone groups, respectively. b P 0.05.

3 VOL. 42, 1998 CEFEPIME VERSUS CEFTRIAXONE FOR PNEUMONIA 731 TABLE 3. Clinical response to therapy for clinically evaluated patients Clinical response (n 40) (n 46) Favorable (cured plus improved) 38 (95.0) 45 (97.8) Cured 8 (20.0) 14 (30.4) Improved 30 (75.0) 31 (67.4) Failure 2 (5.0) 1 (2.2) TABLE 4. Bacteriologic response to therapy for patients evaluated for clinical efficacy a Bacteriologic response (n 32) (n 39) Eradicated 32 (100) 38 (97.4) Documented eradication 17 (53.1) 17 (43.6) Presumed eradication 15 (46.9) 21 (53.8) Persistence 0 (0) 1 (2.6) a Multiple pathogens may have been obtained from the same patient. group, n 1; ceftriaxone group, n 3), the patient missed a study drug dose (cefepime group, n 1), and the patient improved on the physician requested discontinuation (ceftriaxone group, n 1). Although the study protocol excluded patients whose pathogens were not susceptible to the study drug in vitro, there were no discontinuations for this reason because all the organisms were susceptible to the treatments that the patients were randomized to receive. A total of 94 patients completed the study (cefepime group, n 47; ceftriaxone group, n 47). Eighty-six patients were evaluable for clinical efficacy (clinically evaluated patients) (cefepime group, n 40; ceftriaxone group, n 46), and 48 (cefepime group, n 23; ceftriaxone group, n 25) of these patients were evaluable for microbiologic efficacy. Under the study protocol, erythromycin and metronidazole were allowed as concomitant antibiotic therapy when infection with L. pneumophila, M. pneumoniae, C. pneumoniae, or a cephalosporin-resistant anaerobic organism was suspected. During the course of the study, 13 patients in the cefepime group and 15 patients in the ceftriaxone group received erythromycin and 2 patients in each group received metronidazole. Seven additional patients who received concomitant antimicrobial agents were approved by the sponsor as evaluable. The additional antimicrobial agents used were augmentin, bacitracin, doxycycline, and rifampin (one patient each in the ceftriaxone group), trimethoprim-sulfamehoxazole (Bactrim DS) (one patient in the cefepime group), and vancomycin (1 patient in the cefepime group and one patient in the ceftriaxone group). Of the patients included in evaluations of clinical response, comparable numbers in each group received concomitant antibiotics (cefepime group, n 12; ceftriaxone group, n 14). Clinical response. The mean duration of treatment for all patients enrolled in the study was approximately 6.5 days (range, 2 to 14 days). A satisfactory clinical response (cure or improvement) was achieved in 38 of 40 (95.0%) patients in the cefepime group and 45 of 46 (97.8%) patients in the ceftriaxone group (P 0.549) (Table 3). The 95% confidence interval (CI) for the difference between cure plus improvement rates in the two treatment groups (data for the ceftriaxone group minus data for the cefepime group) was determined to lie between 5.1 and 10.8%. Similar results were obtained in an intent-to-treat analysis of all randomized patients: a satisfactory clinical response was achieved in 49 of 59 (83.0%) of all randomized patients in the cefepime group and 50 of 56 (89.3%) of all randomized patients in the ceftriaxone group (P 0.307; 95% CI for difference between groups [data for the group cefepime minus data for the ceftriaxone group], 18.8 to 7.9%). The favorable clinical response (cure plus improvement) rate for those who received concomitant antibiotics was 100% (12 of 12) for the cefepime group and 92.9% (13 of 14) for the ceftriaxone group. In comparison, for patients who did not receive concomitant antibiotics, the favorable clinical response rate was 92.9% (26 of 28) for the cefepime group and 100% (32 of 32) for the ceftriaxone group. The difference in response rates between those who did and those did not receive concomitant antibiotics was statistically insignificant (P 0.974, 0.593, and for all patients included in efficacy analyses, the patients in the cefepime group, and the patients in the ceftriaxone group, respectively). Thus, concomitant antibiotics appeared to have little impact on the efficacies of the study drugs. Bacteriology and bacteriologic response. All organisms isolated demonstrated in vitro susceptibility to the assigned study treatments. The bacteria most frequently isolated from the clinically evaluated patients in the cefepime and ceftriaxone treatment groups were S. pneumoniae (seven and eight isolates, respectively), H. influenzae (nine isolates in each group), and S. aureus (six isolates in each group). The 48 clinically evaluated patients with a microbiologic response included 23 patients with 32 pathogens in the cefepime group and 25 patients with 39 pathogens in the ceftriaxone group. Both treatment groups had similar satisfactory bacteriologic response rates by patient and by pathogen (Tables 4 and 5, respectively). For the cefepime group, all 32 (100%) pathogens were eradicated (documented or presumed eradication). Similar results were noted for the ceftriaxone group, TABLE 5. Bacteriologic response by pathogen for patients evaluated for clinical efficacy a Pathogen No. of patients in the following group with the indicated response b : (n 32), eradication (n 39) Eradication Persistence Enterobacter cloacae 1 Escherichia coli 3 2 Haemophilus influenzae 9 9 Haemophilus parahemolyticus 1 3 Haemophilus parainfluenzae 1 3 Haemophilus species 1 1 Klebsiella pneumonia 1 Lactobacillus species 1 Pseudomonas aeruginosa 1 Pseudomonas fluorescens 1 1 Staphylococcus aureus 6 6 Streptococcus ( -hemolytic) 2 Streptococcus faecalis 1 Streptococcus (group C) 1 Streptococcus pneumoniae 7 9 a Multiple pathogens may have been from the same patient. b No organisms persisted in the cefepime group. Eradication was documented or presumed.

4 732 ZERVOS ET AL. ANTIMICROB. AGENTS CHEMOTHER. with 38 of 39 (97.4%) pathogens eradicated (P 0.317; 95% CI for difference in favorable bacteriologic response rates for ceftriaxone minus the rates for cefepime, 7.5 to 2.4%). The one pathogen that did not respond to therapy with ceftriaxone was Pseudomonas fluorescens, which was found to persist at the posttherapy evaluation. Safety evaluation. An analysis of adverse events was performed for all patients who received at least one dose of study medication (all randomized patients). Treatment-emergent adverse events occurred in 40 of 59 (67.8%) patients treated with cefepime and 29 of 56 (51.8%) patients treated with ceftriaxone (P 0.090). There were no statistically significant differences between the treatment groups for any adverse event category. Six adverse events in the cefepime group and four adverse events in the ceftriaxone group were considered to be probably related to study drug. In the cefepime treatment group, these events included enlarged abdomen, fever, arm pain, abdominal pain, dyspepsia, and urinary tract infection. In the ceftriaxone treatment group, adverse events probably related to study drug were two incidents of diarrhea and one incident each of moniliasis (Candida) and oral moniliasis. Seven cefepime-treated and seven ceftriaxone-treated patients received one to six doses of study drug i.m. Poor tolerance to the i.m. injection was reported for one patient who received ceftriaxone; all other patients in both groups tolerated the i.m. injections well. No clinically significant laboratory abnormalities were reported for either treatment group. Three cefepime-treated patients and one ceftriaxone-treated patient died during the study. None of the deaths was considered to be related to the study treatments. DISCUSSION Current therapeutic strategies for the treatment of pneumonia are complicated by the changing etiologies of this disease. In particular, gram-negative pathogens have become increasingly important as the cause of pneumonia, particularly in patients who are elderly, who are hospitalized, or who have coexisting illnesses, and antibiotic resistance appears to be increasing steadily among respiratory tract pathogens (5 7, 17). These factors, combined with the frequent absence of a microbiologic diagnosis, can confound the selection of an antibiotic for empiric use in the treatment of pneumonia. This study compared an extended-spectrum cephalosporin, cefepime, with a widely used expanded-spectrum cephalosporin, ceftriaxone, for the empiric treatment of hospitalized patients with community-acquired pneumonia. The majority of patients in both treatment groups achieved a satisfactory clinical response: 95.0% of the cefepime-treated and 97.8% of the ceftriaxone-treated clinically evaluated patients were cured or improved. These rates are similar to those reported in previous studies for patients with pneumonia treated with cefepime (80 to 100%) (2, 3, 12, 15) or ceftriaxone (70 to 90%) (1, 9). High bacteriologic response rates were also achieved in both the cefepime and the ceftriaxone groups (100 and 97.4%, respectively, for clinically evaluated patients with a microbiologic response). Although certain concomitant antibiotics (primarily erythromycin and metronidazole) were allowed during this trial, concomitant treatment appeared to have little impact on the favorable clinical response rate in the clinically evaluated patients (cefepime group, 100% with and 92.9% without concomitant antibiotics; ceftriaxone group, 92.9% with and 100% without concomitant antibiotics). The only case of documented persistence of a pathogen occurred in a ceftriaxone-treated patient infected with P. fluorescens. Gram-negative pathogens are increasingly playing a role as the cause of pneumonia, particularly in elderly or hospitalized patients (5, 6). Although a larger study is required to assess the comparative efficacies of cefepime and ceftriaxone against pneumonia caused by gram-negative bacteria or pathogens resistant to multiple antimicrobial agents, in vitro studies have demonstrated that cefepime s activity against certain key gram-negative pathogens, particularly Pseudomonas species and the members of the family Enterobacteriaceae, is superior to that of ceftriaxone (6, 18, 19). In one survey of 12,574 clinical isolates, cefepime was active against 92.7% of all gramnegative bacteria whereas ceftriaxone was active against 74.1% of all gram-negative bacteria (19). Furthermore, for some pathogens cefepime is associated with a lower level of drug resistance than ceftriaxone and other expanded-spectrum cephalosporins. In the survey discussed above, approximately 35% of the Enterobacter cloacae strains were resistant to ceftriaxone, whereas only 4% were resistant to cefepime (19). These data are supported by the results of clinical studies. Of 16 patients infected with strains of Enterobacter spp. with reduced susceptibility or resistance to the expanded-spectrum cephalosporin ceftazidime, all were successfully treated with cefepime (16). Both cefepime and ceftriaxone eradicated 100% of grampositive pathogens from clinically evaluated patients with a microbiologic response. This finding agrees with the antimicrobial activities of these drugs determined in vitro. In these studies, cefepime and ceftriaxone have demonstrated similar levels of activity against gram-positive bacteria commonly associated with community-acquired pneumonia, including S. pneumoniae, H. influenzae, and S. aureus (8). Of particular note are the activities of these agents against penicillin-resistant strains of S. pneumoniae, an important clinical pathogen. In a study involving 122 penicillin-resistant (MICs, 2.0 mg/ liter) or relatively resistant (MICs, 0.12 to 1.0 mg/liter) S. pneumoniae isolates, 95.1% were susceptible to cefepime and 94.3% were susceptible to ceftriaxone (21). In this trial, both cefepime and ceftriaxone were well tolerated, with a low incidence of drug-related adverse events. The favorable safety profile of cefepime has been extensively documented in clinical trials (14). Although this trial did not include sufficient numbers of patients to detect subtle differences in efficacy and safety between cefepime and ceftriaxone, the data reported here support the conclusion that cefepime and ceftriaxone are therapeutically comparable for the empiric treatment of community-acquired pneumonia in hospitalized patients. 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