Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a fourth-generation cephalosporin

R. F. Grossman, D. A. Campbell, S. J. Landis, G. E. Garber, G. Murray, H. G. Stiver, R. Saginur, R. A. McIvor, J. Laforge, C. Rotstein, J. Dubois, M. Rivard and F. Boulerice

Mount Sinai Hospital, Suite 640, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In a prospective, multicentre double-blind trial, 151 patients over the age of 65 years were randomly assigned to receive either cefepime 2 g every 12 h for a minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum of 3 days and up to 14 days. Antibiotics were maintained until 48 h after fever had resolved; no other antibiotics were permitted. The average age in each group exceeded 77 years and significant co-morbidity was found in the majority of patients. The mean total duration of therapy was 5.8 ± 2.4 days for the cefepime group and 6.7 ± 2.7 days for the ceftriaxone group (P= 0.06). The clinical success rate at the end of therapy was 79.1% with cefepime and 75.4% with ceftriaxone (P= 0.62). At the end of follow-up, 91.7% of the cefepime-treated patients and 86.5% of the ceftriaxone patients had a satisfactory clinical response (P= 0.38). In 35 bacteriological evaluable patients, potential pathogens were eradicated in all but one patient receiving cefepime. Seven patients in each group died during the study period but in each case the death was unrelated to study drug. The commonest side-effect was diarrhoea (cefepime, five patients; ceftriaxone, two patients). The clinical and microbiological efficacy of cefepime is similar to that of ceftriaxone in elderly patients with community-acquired pneumonia requiring hospitalization. Cefepime is an appropriate choice for the treatment of community-acquired respiratory tract infections in the elderly.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Community-acquired pneumonia affects approximately 4 million adults in the USA annually, leading to 600,000 hospitalizations.1 Current life expectancy is 80 years for women and 73 years for men.2 The elderly (age >65 years) are hospitalized frequently for community-acquired respiratory tract infections with an admission rate of 11.5 per 1000 population.3 In 1990, their mortality rate was 198 per 100,000 population representing 90% of deaths from pneumonia for all ages. Several studies have demonstrated that age >65 years is associated with a poor outcome although separating age as a risk factor from other co- morbidity is difficult.456

The common bacterial agents associated with community-acquired pneumonia are Streptococcus pneumoniae, Haemophilus influenzae and Mycoplasma pneumoniae. More recently, other pathogens such as Chlamydia pneumoniae, Moraxella catarrhalis and Legionella pneumophila have been identified. In studies involving the elderly, the commonest pathogens appear to be S. pneumoniae and H. influenzae.789Gram-negative organisms colonize the oropharynx more commonly in the elderly and it is suspected that Gram-negative infection is more important in the elderly, especially among patients with respiratory impairment or immobility, and in those from nursing homes.10

Treatment with cephalosporins (either second- or third-generation) has been recommended as first-line empirical therapy for elderly patients with community-acquired pneumonia. 11 With the increasing development of resistance to first-line agents, alternative choices are required. Resistance even to third-generation cephalosporins has been demonstrated among Enterobacter and Klebsiell{alpha} spp. 12,13 These organisms have extended-spectrum ß- lactamases mainly of type TEM-1, TEM-2 or SVH-1, the common plasmid-determined ß-lactamases that confer resistance to penicillins and early generation cephalosporins.14 Cefepime, a novel fourth-generation cephalosporin, has low affinity for major chromosomally-mediated ß-lactamases and retains good activity against Pseudomonas aeruginosa and Staphylococcus aureus.15 With an MIC90 of 0.05 mg/L against S. pneumoniae, cefepime is more active than ceftazidime, and similar to cefotaxime. 16 The drug is extremely active against H. influenzae (MIC 90 range 0.06–0.25 mg/L) and is not influenced by the production of ß-lactamase.17 Unlike imipenem and some second- generation cephalosporins, cefepime is a poor inducer of type I ß-lactamases. 17 It penetrates the outer membrane of Enterobacter cloacae and Escherichia coli at least three times more quickly than cefotaxime, ceftazidime or ceftriaxone.18 This study was performed to compare the clinical efficacy and safety of cefepime with those of ceftriaxone in the treatment of elderly subjects with community-acquired bacterial pneumonia.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient selection

Adult patients, aged >=65 years, who had been admitted to the hospital after developing pneumonia in the community or in a nursing home or extended care facility were eligible for enrolment. Patients had to have radiological findings consistent with pneumonia and physical findings of consolidation or other signs of pulmonary involvement (dullness to percussion, bronchial breath sounds, increased respiratory rate or crackles). In addition they had to demonstrate one or more of the following: fever (buccal temperature >37.8°C), leucocytosis (white blood cell count >11 x 109/L and/or left shift), chest pain or cough. The following were excluded from the study: patients with infections due to organisms known to be resistant to a study drug before study entry; patients with hospital-acquired pneumonia; patients with renal impairment with an estimated creatinine clearance <11 mL/min, who had acute loss of renal function, or who were receiving peritoneal dialysis, haemodialysis or plasmapheresis; patients with granulocytopenia (white blood cell count <1 x 109/L) or thrombocytopenia (<50 x 109/L); patients with a terminal illness that would limit survival during therapy and the follow-up period; patients with cystic fibrosis or pneumonia for which >14 days of therapy would be required (post-obstructive pneumonia, empyema); patients with bacterial infections or severe burns; patients with concurrent meningitis, osteomyelitis or infective endocarditis; patients with HIV-positive status; patients with gall-bladder disease; patients with serious hepatic disease defined as a greater than three-fold elevation in transaminase levels, bilirubin levels >52 µm/L (3 mg/dL) or presence of hepatic encephalopathy; patients with documented legionella, mycoplasma, chlamydia or anaerobic pneumonia before study enrolment; patients with confirmed or suspected P. aeruginosa infection; patients with a history of hypersensitivity to ß-lactam or cephalosporin antibiotics; patients receiving HA-1A, E-5 or anti-TNF monoclonal antibody therapy for sepsis; patients who had received parenteral antibiotic therapy within 7 days before starting therapy with study drug; patients who had received oral antimicrobial therapy within 24 h unless there had been no clinical response; patients who had previously received cefepime or ceftriaxone for this illness within 30 days of entry. Each centre's institutional review board approved the study, and all patients provided written informed consent.

Study design and antimicrobial therapy

This was a multicentre, prospective, randomized, double-blind trial. Patients were randomly assigned to two groups of equal size, to receive either cefepime 2 g every 12 h for a minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum of 3 days and up to 14 days. Pharmacists adjusted the dosage of cefepime in the presence of a reduced creatinine clearance. The study investigators were kept unaware of dosage alterations. Antibiotic therapy was maintained until at least 48 h after the resolution of fever. No other antibiotics were permitted.

Microbiological investigations

A sputum sample for routine culture and Gram's stain were obtained within 48 h before the start of therapy. Identification of causative organisms and testing for susceptibility to both study drugs by disc and/or MIC methods were performed according to NCCLS standards. 19,20 Two sets (aerobic and anaerobic) of blood cultures were obtained from different sites within 48 h before the initiation of therapy. Isolates were deemed susceptible to cefepime if the disc zone was >=18 mm or the MIC was <=8 mg/L. Isolates were considered resistant to cefepime if the disc zone was <=14 mm or the MIC was >=32 mg/L. Susceptibility ranges taken from the product monograph were used to identify susceptibility to ceftriaxone. Testing for the so-called `atypical pathogens', M. pneumoniae, C. pneumoniae and Legionella spp., was not performed.

Clinical and microbiological evaluations

The efficacy analysis was based on the clinical and bacteriological responses at the end of study drug therapy. Secondary analyses included the time to cessation of iv therapy and the proportion of patients who switched to oral therapy.

Clinical assessment was based on changes in signs and symptoms from the pre-treatment presentation and the changes in the chest X-rays taken before and after completion of therapy. The clinical response at the end of therapy was categorized as `cured' (resolution of signs and symptoms of original infection plus improvement or lack of progression in chest X-ray findings), `improved' (incomplete resolution of signs, symptoms and chest X-ray findings), `failure' (no response to therapy) or `indeterminate' (no evaluation possible). At the second post-therapy visit (10–14 days after completion of therapy) a similar analysis of clinical response was made with the additional category of `relapse' (new, reappearing or worsening signs and symptoms of pneumonia).

Safety evaluations

All patients who had received at least one dose of study drug were evaluated for drug safety. Adverse events were categorized by the investigator by their severity and relationship to study drug. Laboratory tests were performed before therapy, during therapy, on the final day of therapy and, if clinically indicated, 10–14 days after completion of therapy.

Statistical analysis

The primary objective of this study was to determine if cefepime therapy was statistically equivalent to therapy with ceftriaxone in terms of clinical and microbiological results. In a previous study with ceftriaxone, an overall success rate of 92% was achieved. 21 Based on an assumption of equivalence between treatments, 69 evaluable patients in each arm would assure with 90% probability that the upper limit of the 95% confidence interval for the true difference in the clinical response rate between the two treatments would not exceed 15%. With a 90% evaluability rate, 153 subjects would have to be enrolled.

The demographics and baseline medical characteristics of patients in the two groups were compared to assess the homogeneity of the two treatment groups. Categorical variables were analysed using Pearson {chi}2 tests or Fisher's exact tests, and continuous variables were analysed using t-tests. Efficacy analyses included the evaluation at post-treatment and at follow-up of clinical response and, in appropriate patients, bacteriological response. The statistical significance of the differences in clinical response rates of cure plus improvement between the two treatment groups were evaluated with Pearson {chi}2 tests; 95% confidence intervals for the true differences in clinical response rates were also constructed. Differences in bacteriological response rates were analysed with Pearson {chi}2 tests. Differences in rates of adverse events were also analysed with Pearson {chi}2 tests.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The intent-to-treat population consisted of 151 patients enrolled in 15 centres; 76 patients received cefepime while 75 patients received ceftriaxone. Two patients (one in each group) had missing data on all or most parameters and could not be assessed. The demographic and baseline characteristics of the intent-to-treat group were comparable for the cefepime and ceftriaxone treatment populations. The demographic and baseline characteristics of patients included in the groups evaluable for efficacy were found to be similar for the two treatment groups and were comparable to those of the intent-to-treat population. The data presented are from the clinically evaluable patients (Table I). The average age of patients in each group exceeded 77 years. Significant pulmonary and cardiovascular co-morbidity was present in the majority of patients. Seven patients in each treatment arm died during the course of the study.


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Table I. Demographic and baseline characteristics of the clinically evaluable patients
 
Sixty-seven patients in the cefepime arm and 61 patients in the ceftriaxone arm were considered to be evaluable at the post-treatment evaluation. The reasons that patients were considered clinically unevaluable included loss to follow-up (two receiving cefepime and one receiving ceftriaxone), early drug discontinuation due to adverse events (three receiving ceftriaxone), protocol violation— unconfirmed clinical diagnosis (three receiving cefepime and five receiving ceftriaxone), protocol violation— patient received other antimicrobial agent during study (one receiving cefepime and three receiving ceftriaxone), protocol violation— no post-treatment chest X-ray (three receiving cefepime and one receiving ceftriaxone) and protocol violation— parenteral antibiotic given within 7 days before onset of study drug therapy (one receiving ceftriaxone).

The mean total duration of therapy was 5.8 ± 2.4 days for the cefepime group and 6.7 ± 2.7 days for the ceftriaxone group (P = 0.06). The cefepime group received 10.4 ± 4.9 doses while the ceftriaxone group received 11.9 ± 5.3 doses (P= 0.09).

The commonest bacterial pathogens among clinically evaluable patients were S. pneumoniae (isolated from 25 patients), H. influenzae (isolated from nine patients), M. catarrhalis (isolated from seven patients) and S. aureus (isolated from six patients) and other Gram-negative organisms (Haemophilus parainfluenzae from three patients, Serratia marcescens from two patients, and K. pneumoniae, Enterobacter aerogenes, P. aeruginosa, E. coli, Stenotrophomonas maltophilia each isolated from one patient). More than one species of pathogen was found in 12 patients.

The clinical success rates (cure or improvement) at the end of therapy was 79.1% for the cefepime group and 75.4% in the ceftriaxone group (P= 0.62). While the treatment difference was 3.7% in favour of cefepime, the 95% confidence interval (-10.9% to 18.2%) suggested that the two treatments were equivalent. Twelve patients (17.9%) in the cefepime arm and 15 patients (24.6%) in the ceftriaxone arm were considered clinical failures.

The evaluation of clinical response at follow-up indicated that 91.7% of the cefepime patients and 86.5% of the ceftriaxone patients had a satisfactory (cured or improved) clinical response (P= 0.38). The rate difference was 5.1% with a 95% confidence interval of -6.5% to 16.8%. The investigators' evaluation of clinical response indicated a high rate of treatment success with both therapies (98.3% for cefepime-treated patients and 90.4% for ceftriaxone-treated patients; P= 0.07).

A total of 46 pre-therapy causative pathogens were isolated from the 35 bacteriological evaluable patients (18 in the cefepime arm and 17 in the ceftriaxone arm). In all patients except for one receiving cefepime, the baseline pathogens were eradicated. In the one exception, the patient had S. pneumoniae and M. catarrhalis isolated at the beginning of the study. At the end of the study, M. catarrhalis persisted and the patient was classified as having a persistent pathogen.

At the late follow-up visit, new infections were documented in six patients receiving cefepime (one Clostridium difficile, one oral herpes simplex, one lower respiratory tract infection, one skin lesion, one pneumonia and one rhinorrhoea) and in five patients receiving ceftriaxone (one cystitis, one breast infection, one urinary tract infection, one skin lesion and one pneumonia).

Adverse events

Adverse events were commonly reported in both groups (cefepime, 76.3%; ceftriaxone, 84.0%) but there was no statistically significant difference between them (P= 0.24) (Table II). In the cefepime-treated patients 3.6% of all adverse events were classified as probably or possibly related to study drug while in the ceftriaxone-treated patients 4.1% were similarly classified. While 19.8% of the adverse events in the cefepime arm were judged severe or very severe, none were thought to be related to the medication. Similarly, in the ceftriaxone-treated patients, 19.1% of the adverse events were graded severe or very severe and only one was thought to be possibly related to the medication. The commonest side-effect thought to be related to study medication was diarrhoea (cefepime, five patients; ceftriaxone, two patients). Seven patients in each group died during the study period, but in each case the investigator considered the death as unrelated or unlikely to be related to the study drug.


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Table II. Adverse events reported by body system
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This multicentre, randomized, double blind controlled trial demonstrated that cefepime was effective in the management of elderly patients admitted to hospital with community-acquired bacterial pneumonia. The clinical and microbiological efficacy of cefepime was similar to that seen with ceftriaxone. The overall mortality rate of 9.3% is low considering the age of the patients, the severity of the disease and presence of co-morbid illnesses.

It is difficult to be specific regarding the choice of antimicrobials in the elderly with community-acquired pneumonia. Most studies have enrolled a heterogeneous group of patients whose microbiology has not been well documented. Marrie and co-workers 22 were able to obtain sputum samples in only 31% of nursing home patients with pneumonia and pathogens were isolated in <50%. In this current study, S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus and other Gram-negative organisms were the most commonly isolated pathogens. Only 27% of the clinically evaluable patients were also microbiologically evaluable. In another study of nursing home pneumonia, S. pneumoniae, H. influenzae and other Gram-negative organisms were the most commonly isolated.23

This study has demonstrated that cefepime has predictable activity against the major pathogens associated with community-acquired pneumonia in the elderly. In this era of cost containment, the trend of patients receiving cefepime to require fewer days of therapy and to receive fewer iv doses of antimicrobial therapy may be advantageous. The ability to switch to oral therapy after only a few days of iv therapy is desirable. Another factor that will assist the practitioner in selecting an antimicrobial agent is the favourable side-effect profile of cefepime. Mild gastrointestinal events (diarrhoea) were the most commonly reported side-effects but serious side-effects thought to be related to the medication did not occur in the patients receiving cefepime.

Cefepime is a `fourth-generation' cephalosporin: it has a broader spectrum of antibacterial activity than the third-generation cephalosporins and is more active in vitro against Gram-positive aerobic bacteria.15 Previous studies have demonstrated that cefepime is as effective as cefta- zidime or cefotaxime in the treatment of nosocomial and community-acquired lower respiratory tract infections. 24,25 Given its relative efficacy compared with other third- generation cephalosporins, the enhanced stability of cefepime against some ß-lactamases, its favourable pharmacokinetics and side-effect profile make it an appropriate choice for the treatment of community-acquired respiratory tract infections in the elderly.


    Acknowledgments
 
This study was funded by a Grant-in-aid from Bristol-Myers Squibb.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Bartlett, J. G. & Mundy, L. M. (1995). Community-acquired pneumonia. New England Journal of Medicine 333, 1618–24.[Free Full Text]

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12 . Chow, J. W., Fine, M. J., Shlaes, D. M., Quinn, J. P., Hooper, D. C., Johnson, M. P. et al. (1991). Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Annals of Internal Medicine 115, 585–90.[ISI][Medline]

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18 . Hancock, R. E. W. & Bellido, F. (1992). Factors involved in the enhanced activity against Gram-negative bacteria of fourth generation cephalosporins. Journal of Antimicrobial Chemotherapy 29, Suppl. A, 1–6.[ISI][Medline]

19 . National Committee for Clinical Laboratory Standards. (1988). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved Standard M7-A1. NCCLS, Villanova, PA.

20 . National Committee for Clinical Laboratory Standards. (1983). Performance Standards for Antimicrobial Disc Susceptibility Tests— Third Edition: Approved Standard M2-A3. NCCLS, Villanova, PA.

21 . Zuck, P., Rio, Y. & Ichou, F. (1990). Efficacy and tolerance of cefpodoxime proxetil with ceftriaxone in vulnerable patients with bronchopneumonia. Journal of Antimicrobial Chemotherapy 26 , Suppl. E, 71–7.[Abstract]

22 . Marrie, T. J., Durant, H. & Kwan, C. (1986). Nursing home-acquired pneumonia. A case-control study. Journal of the American Geriatric Society 34, 697–702.[ISI]

23 . Hirata-Dulas, C. A., Stein, D. J., Guay, D. R., Gruninger, R. P. & Peterson, P. K. (1991). A randomized study of ciprofloxacin versus ceftriaxone in the treatment of nursing home-acquired lower respiratory tract infections. Journal of the American Geriatric Society 39, 979–85.[ISI]

24 . McCabe, R., Chirurgi, V., Farkas, S. A., Haddow, A., Heinz, G. & Greene, S. (1996). A new therapeutic option for the treatment of pneumonia. American Journal of Medicine 100 , Suppl. 6A, 60S–7S.

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Received 11 May 1998; returned 3 July 1998; revised 27 August 1998; accepted 9 December 1998