The Journal of International Medical Research 2004; 32: 84 – 93

Cefepime versus Ceftazidime for Treatment of Pneumonia K KONSTANTINOU1, K BADDAM1, A LANKA1, K REDDY1

AND

M ZERVOS1,2

1Department

of Medicine, Division of Infectious Diseases, William Beaumont Hospital, Royal Oak, MI, USA; 2Wayne State University, Detroit, MI, USA (VRE) and resistance to therapy. Posttherapy hospitalization (days) and vancomycin co-administration were significantly lower, and time to vancomycin initiation significantly higher, in the cefepime compared with the ceftazidime group. The results suggest a trend towards less resistance on therapy, less VRE, reduced vancomycin use and shorter posttherapy hospitalization in patients treated with cefepime compared with ceftazidime. The clinical outcomes for hospitalized patients treated for serious pneumonia were similar between the two groups.

Consecutive patients with pneumonia, treated with cefepime (n = 66) or ceftazidime (n = 132), were evaluated in a retrospective, observational study. There was no significant difference between the two treatment groups with respect to age, underlying diseases, acute physical and chronic health evaluation score, intensive care unit admission, presence of sepsis, community or hospital acquisition, causative organism, duration of therapy, death, cure or improvement in infection, adverse events, superinfections, presence of vancomycin-resistant enterococcus

KEY WORDS: CEFEPIME; CEFTAZIDIME; COMMUNITY-ACQUIRED HOSPITAL-ACQUIRED PNEUMONIA

PNEUMONIA;

Increasingly, only the most severely ill and immunocompromised patients are admitted to hospital. This has caused what were formerly hospital-specific treatments and risk factors to shift to the out-patient setting. Frequent patient readmissions, specialized out-patient units and increasing numbers of nursing-home patients in various types of skilled and non-skilled facilities further complicate the ability to define hospitalversus community-acquired pneumonia. Increasing antimicrobial resistance has occurred among pneumonia-causing pathogens. Increasing hospitalization costs require clinicians to consider the cost of medical care interventions. These factors

Introduction Pneumonia is a common problem resulting in significant morbidity, mortality and costs related to medical care.1 – 7 In the USA, pneumonia is the leading cause of infectionrelated mortality and community-acquired pneumonia occurs in at least four million people annually, resulting in over 600 000 hospital admissions.1 – 4 Hospital-acquired pneumonia is the second most common nosocomial infection, with mortality rates of up to 60%.8 Defining community- and hospital-acquired pneumonia using classic definitions is becoming more difficult because of a changing hospital environment.

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia incubating on admission. Patients with a prior hospital admission within 14 days or those admitted from a nursing home were considered to have hospital-acquired pneumonia. Hospital-acquired pneumonia was further defined as present when there was a new or changing infiltrate, predominant organism on Gram-stain with > 25 polymorphonuclear leukocytes (PMNs) and < 10 epithelial cells per low-power field (LPF), an increased volume of sputum, or deterioration of respiratory function not attributable to another cause. Evidence of community-acquired pneumonia was defined by the presence of pulmonary infiltrates or other radiological findings consistent with the diagnosis of pneumonia, physical examination findings, fever (temperature > 38 °C) or hypothermia (temperature < 36 °C), purulent sputum (> 25 PMNs and < 10 squamous cells/ LPF) and leukocytosis (leukocyte count > 10 000/mm3). Patients with neutropenia (< 1000 PMNs) were excluded. Demographic data were recorded from the patient records. Patient management was at the discretion of the physician caring for the patient. Vancomycin treatment was started following the Centers for Diseases Control guidelines,14 with use monitored by the hospital pharmacy. No changes were made in hospital admission policies over the study period. Investigators performing the outcome assessment were blinded to the drug administered. This was a retrospective study so patient consent was not sought.

contribute to an increased difficulty in defining the most appropriate treatments for patients presenting with pneumonia. Treatment guidelines for managing community-acquired pneumonia have suggested that the spectrum of antimicrobial agents be broadened when patients are seriously ill or have serious co-morbid illness, but there is limited comparative information on the outcome of these interventions.9 – 12 Both cefepime and ceftazidime are approved in the USA and Europe for treatment of pneumonia. Guidelines have recommended their use for therapy when pseudomonas is suspected (i.e. when there is a history of obstructive lung disease).9 – 12 The aim of this study was to evaluate the clinical outcome of hospitalized patients with pneumonia treated with cefepime or ceftazidime.

Patients and methods STUDY DESIGN AND PATIENTS This study was approved by the William Beaumont Hospital Human Investigation Committee and was conducted at the William Beaumont Hospital, a 999-bed acute-care community teaching hospital. Cefepime was added to the hospital formulary in 1997. As part of a hospital-wide substitution policy, all subsequent orders for ceftazidime were automatically substituted with cefepime. This retrospective, case-controlled study was conducted over a 3-year period between May 1997 and May 2000 and compared patients with pneumonia, with and without sepsis, treated with cefepime or ceftazidime. Patients treated with ceftazidime were matched 1:2 with patients treated with cefepime. Previously published definitions of pneumonia were used.13 Hospital-acquired pneumonia was defined as that occurring > 72 h after hospital admission and not

LABORATORY ANALYSES Respiratory secretions were cultured for routine respiratory pathogens by the clinical microbiology laboratory, using standard procedures. Susceptibility to cefepime and ceftazidime was determined by minimum inhibitory concentration methods using

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia National Committee for Clinical Laboratory Standards guidelines.15

the Cochran-Mantel-Haenszel test (clinical and microbiologic response rates), and quantitative variables by two-way analysis of variance. A P-value < 0.05 was considered statistically significant.

EVALUATION OF EFFICACY: OUTCOME ASSESSMENTS Patients were considered clinically evaluable if they received a study drug for at least 5 days. The clinical response of each patient was categorized on day 30: cure – complete resolution of all signs and symptoms of pneumonia and improvement or lack of progression of all positive findings on chest radiography; relapse – recurrence of one or more signs and symptoms of pneumonia after completion of therapy; failure – failure to resolve signs and symptoms of pneumonia or progression of infection on chest radiography; superinfection or colonization – any pathogens, other than the original organism, isolated from cultures during therapy or within 3 days of completion of therapy were judged to be superinfections or colonization. The microbiologic response to treatment was defined as: eradication – elimination of the original pathogen(s) from subsequent cultures; 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 and clinical cure; 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.

Results Demographic and clinical characteristics of the 198 patients studied are shown in Table 1. Patients in the two treatment groups were similar for all measurements. The organisms causing pneumonia are shown in Table 2. Pseudomonas aeruginosa and other Gram-negative bacteria were the most common organisms isolated, and were found at a similar frequency in the two treatment groups. A summary of outcome measurements for each treatment group is shown in Table 3. Clinical and microbiologic cure occurred in 63.6% and 58.3% of the cefepime- and 56.1% and 45.5% of the ceftazidime-treated patients, respectively. Superinfections occurred in 18 patients (13.6%) in the cefepime group (eight patients with methicillin-resistant coagulasenegative Staphylococcus, six with methicillinresistant Staphylococcus aureus, two with Candida albicans and two patients with other organisms). There were VRE superinfections in 11 patients (16.7%) in the ceftazidime group (four patients with methicillin-resistant coagulase-negative Staphylococcus, four with vancomycin-resistant Enterococcus faecium and three patients with methicillin-resistant S. aureus) but none in the cefepime group.

Discussion

STATISTICAL ANALYSIS Statistical analyses were performed to compare demographic and baseline medical characteristics, severity of illness, efficacy and safety. In assessing the comparability of the two treatment groups, categorical variables were analyzed by either Fisher’s exact test (incidence of adverse events) or

Pneumonia is the major cause of infectionrelated death in the USA. Despite significant progress and extensive literature on methods for detecting pathogens and therapeutic options, there remains considerable controversy in the management of this disorder.13 – 30 Recent consensus guidelines for

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia

TABLE 1: Demographic and clinical characteristics of 198 patients with community- or hospitalacquired pneumonia treated with cefepime or ceftazidime in this retrospective study Cefepime

Ceftazidime

Community

Hospital

Total

Community

Hospital

Total

Patient number (%)

68 (51.5)

64 (48.5)

132

34 (51.5)

32 (48.5)

66

Mean age (y) [range]

65.3 [19 – 94]

66.6 [34 – 86]

66.0 [19 – 94]

66.1 [40 – 81]

69.3 67.7 [35 – 92] [35 – 92]

Percentage with underlying disease* Pulmonary Cardiovascular Cancer Diabetes

100 52.9 32.3 14.7 20.6

100 59.3 40.6 25.0 28.1

100 56.0 36.4 19.7 24.2

100 58.8 35.3 17.6 8.8

100 68.7 43.7 31.2 9.3

100 63.6 39.4 24.2 9.1

Mean APACHE II score

19.4

22.6

21.0

19.6

21.7

20.7

Percentage admitted to the ICU

32.3

46.9

39.4

23.5

46.9

34.8

Percentage with sepsis

33.8

37.5

35.6

32.3

34.4

33.3

APACHE II, acute physical and chronic health evaluation II scores; ICU, intensive care unit. *More than one underlying disease was present in some patients. P ≥ 0.05 for all comparisons.

managing community-acquired pneumonia have been published by the American Thoracic Society (ATS),9 and Infectious Disease Society of America (IDSA).12 ATS guidelines for pneumonia recommend coverage for P. aeruginosa when patients are seriously ill, or for those in the intensive care unit (ICU) with serious pneumonia. The IDSA expert panel preferred agents for community-acquired pneumonia include erythromycin, azithromycin (or a fluoroquinolone with enhanced activity against Streptococcus pneumoniae plus cefotaxime, ceftriaxone or a β-lactamase inhibitor combination). For structural lung disease, an anti-pseudomonal agent is recommended, including piperacillin/tazobactam, ticarcillin/ clavulanate, anti-pseudomonal penicillin, a carbapenem or cefepime plus an aminoglycoside. Gram-negative bacteria were felt to be the causative pathogens in a predominance of

patients in this study, even though over 50% of patients had community-acquired pneumonia. Furthermore, there was no clear difference in the pattern of isolates for hospital- versus community-acquired pneumonia. The spectrum and organisms isolated in this study clearly differ from patients meeting classic definitions for community-acquired pneumonia.16,17 The Pneumonia Severity Index (PSI) was not calculated for each group, but the mean acute physical and chronic health evaluation II scores and underlying diseases were similar between the groups. It is important to note, however, that the demographic and clinical characteristics of our patients with community- and hospitalacquired pneumonia were similar. Both were groups of elderly and severely ill patients, with severe underlying diseases (particularly chronic pulmonary and cardiovascular disease). These diseases are associated with

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia

TABLE 2: Organisms causing community- or hospital-acquired pneumonia isolated at the time of admission in 198 patients subsequently treated with cefepime or ceftazidime in this retrospective study Cefepime (n)

Number of patients Gram-negative organism Pseudomonas aeruginosa (%) Klebsiella pneumoniae (%) Enterobacter species (%) Escherichia coli (%) Other (%) Not Gram-negative organism Staphylococcus aureus (%) Streptococcus pneumoniae (%) Total

Ceftazidime (n)

Community

Hospital

Total

Community

Hospital

Total

68 (51.5)

64 (48.5)

132

34 (51.5)

32 (48.5)

66

20 (29.4)

16 (25.0)

36 (27.3)

9 (26.5)

10 (31.3) 19 (28.8)

8 (11.8)

6 (9.4)

14 (10.6)

5 (14.7)

2 (6.3)

7 (10.6)

6 (8.8) 6 (8.8) 4 (5.9)

8 (12.5) 8 (12.5) 4 (6.3)

14 (10.6) 14 (10.6) 8 (6.1)

2 (5.9) 2 (5.9) 1 (2.9)

5 (15.6) 2 (6.3) 1 (3.1)

7 (10.6) 4 (6.1) 2 (3.0)

10 (14.7)

4 (6.3)

14 (10.6)

4 (11.8)

1 (3.1)

5 (7.6)

4 (5.9)

0 (0)

4 (3.0)

2 (5.9)

0 (0)

2 (3.0)

58 (85.3)

46 (71.9) 104 (78.8)

25 (73.5)

21(65.6) 46 (69.7)

Pathogenic organisms were not isolated from every patient.

In this study, patients with severe pneumonia were studied before and after introduction of cefepime to the hospital formulary. Cefepime is a fourth-generation cephalosporin with excellent in vitro activity against multiple drug-resistant Gramnegative bacteria, including Enterobacter species, Klebsiella species, P. aeruginosa and activity against S. pneumoniae that is comparable to ceftriaxone.31 – 43 It is also unique among cephalosporins in that a two-step mutation is required to develop resistance in those organisms that carry the genetic code for induction of β-lactamase. A larger study is required to assess the comparative efficacies of cefepime and ceftazidime against pneumonia caused by Gram-negative bacteria or pathogens resistant to multiple antimicrobial agents. In

many of the risk factors for hospital-acquired pathogens rather than community-acquired infections. The results of this study demonstrate that in this subset of patients (severe community-acquired pneumonia and serious underlying disease) the potential causative pathogens are similar to those found in patients meeting the definitions for hospital-acquired pneumonia. In the USA, the trend towards hospitalizing only the most severely ill, immunocompromised individuals is growing. Many risk factors formerly known to occur in the hospital now occur in the out-patient setting. In view of these changes, the patients observed in this study represent a growing subgroup of patients with serious infection for which more broad-spectrum therapy should be considered.

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia

TABLE 3: Summary of outcome measures observed in patients with pneumonia treated with cefepime or ceftazidime in this retrospective study Cefepime (n) Community Patient number

68

Hospital 64

Ceftazidime (n) Total 132

Community 34

Hospital 32

Total

P

66

Mean duration of therapy (days)

6.2

6.7

6.5

6.5

6.8

6.7

Mean post-therapy hospitalization (days)

6.1

6.4

6.3

9.5

9.9

9.7 0.001

Mean number of days before initiation of vancomycin therapy

4.5

4.7

4.6

2.0

3.2

2.6

0.01

70.6 23.5 5.9

56.3 40.6 3.1

63.6 31.8 4.5

64.7 26.5 8.8

46.9 43.8 9.4

56.1 34.8 9.1

NS NS NS

64.7

51.6

58.3

58.8

31.3

45.5

NS

5.9 0

9.4 0

7.6 0

5.9 2.9

12.5 6.3

9.1 4.5

NS NS

Superinfections 11.8 Vancomycin-resistant enterococcus 0

15.6

13.6

14.7

18.8

16.7

NS

0

0

2.9

9.4

6.1

NS

Co-administration of vancomycin

44.1

46.9

45.5

79.4

84.4

0

0

0

2.9

9.4

Percentage of patients with: Cure or improvement Death Relapse Microbiologic eradication Adverse events Gastrointestinal Allergy

Resistance on therapy

NS

81.8 0.001

6.1

NS

NS, not significant.

vitro studies, however, have demonstrated that cefepime activity against certain key Gram-negative pathogens – particularly Pseudomonas and Klebsiella species and the members of the family Enterobacteriaceae – is superior to that of third-generation cephalosporins.33,41 – 44 In one surveillance study of 12 574 clinical isolates, cefepime was active against 92.7% of all Gram-negative bacteria whereas ceftriaxone

was active against 74.1%.41 For some pathogens, cefepime is associated with a lower level of drug resistance than ceftriaxone and other expanded-spectrum cephalosporins. In this study, approximately 35% of the Enterobacter cloacae strains were resistant to ceftriaxone, whereas only 4% were resistant to cefepime. In another recent study of over 151 bloodstream Enterobacter species isolates submitted from across North

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia hospitalization in patients treated with cefepime, which probably contributed to these observations. Nearly all patients colonized or infected with multiple drugresistant enterococci have been previously treated with antibiotics. The association between prior cephalosporin use and enterococcal superinfection is well established. Any drug, however, that lacks activity against enterococcus is a risk factor for nosocomial acquisition. Few prospective studies have evaluated the relative or independent antimicrobial risks associated with VRE infection.56 – 58 In these studies, cephalosporin administration was not associated with VRE or VRE-related mortality.55 – 57 The results of our study support the observation that the most important antimicrobial risk factor for VRE is prior vancomycin use. Differences in outcome between these two groups of consecutive patients have potentially significant pharmacoeconomic impact, and merit further evaluation in a randomized prospective trial. There is considerable literature on the etiology and management of pneumonia, but there is less information on the comparative cost of care. Our study extends the findings of Ambrose et al.,55 who evaluated the efficacy, safety and costeffectiveness of ceftazidime and cefepime in 100 patients with hospital-acquired pneumonia. In their study, clinical success rates were 60% and 78% for patients treated with ceftazidime and cefepime, respectively (P = 0.05). Microbiologic eradication rates were 55% for ceftazidime and 77% for cefepime (P = 0.04). In patients in whom P. aeruginosa was isolated, the organism was eradicated in 70% of cefepime patients and in 50% of ceftazidime patients. The frequency of concomitant antibiotic use was less in the cefepime group (ceftazidime

America,45 69.4% of Enterobacter isolates were susceptible to ceftazidime while 99.3% were susceptible to cefepime. The usefulness of third-generation cephalosporins may be diminished by the presence of inducible β-lactamases in important nosocomial pathogens such as Enterobacter species, Pseudomonas species and Serratia marcescens.44 – 49 Data from the SENTRY antimicrobial surveillance programme44 revealed a significant proportion of isolates of both nosocomial and community-acquired pathogens exhibit antimicrobial resistance. In this study, 30.6% of Enterobacter species isolates were ceftazidime-resistant. Newer cephalosporins such as cefepime, however, retain activity against the strains of Gramnegative bacilli that produce plasmidmediated β-lactamases.49 – 54 Of 16 patients infected with strains of Enterobacter species with reduced susceptibility or resistance to the expanded-spectrum cephalosporin ceftazidime, all were successfully treated with cefepime.38 These data are consistent with the results of numerous other earlier trials comparing cefepime with ceftazidime in treating serious lower respiratory infections.31 – 33,36 – 39,45 – 48,55 The number of patients we studied was small, but the clinical outcomes were similar between cefepime and ceftazidime for pneumonia. There was, however, a trend toward a better response with cefepime. Three patients receiving ceftazidime developed resistance on therapy compared with none receiving cefepime, although this difference was not significant. Importantly, our results showed that in patients administered cefepime, there were no vancomycin-resistant enterococcus (VRE) superinfections. There was significantly less use of vancomycin, longer time to vancomycin initiation and shorter post-therapy

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K Konstantinou, K Baddam, A Lanka et al. Cefepime versus ceftazidime in pneumonia [74%], cefepime [44%]; P = 0.004), particularly with vancomycin (ceftazidime [22%], cefepime [2%]). Cefepime was more cost-effective than ceftazidime (ceftazidime, $395.93 ± $355.22; cefepime, $266.59 ± $200.17; P = 0.05). Their data and the results of our study support cefepime as a costeffective alternative to ceftazidime as a therapy for severe community-acquired and hospital-acquired pneumonia. Our study suggests that for some patients with community-acquired pneumonia, serious underlying disease and severe pneumonia may be modifying factors, and anti-pseudomonal therapy should be considered. Antimicrobial resistance and changing hospitals have resulted in the need

for new strategies to treat pneumonia. Pneumonia remains a common disease resulting in significant morbidity, mortality and costs related to therapy, and patient costs and outcome should be considered as interrelated. Challenges remain in the optimal approach to management, and more research is needed to further optimize cost-effective therapy and enable specific etiological diagnosis so that appropriate therapy can be directed. Effective strategies to control antimicrobial resistance are also needed.

Acknowledgement Supported in part by Elan Pharmaceutical Company.

• Received for publication 27 June 2003 • Accepted subject to revision 4 July 2003 • Revised accepted 17 September 2003 Copyright © 2004 Cambridge Medical Publications Gandola L, Valenti G, et al: Comparative efficacy of ceftriaxone versus ceftazidime in the treatment of nosocomial lower respiratory tract infections. Chemotherapy 1991; 37: 371 – 375. 9 Niederman MS, Bass JB, Campbell GD, Fein AM, Grossman RF, Mandell LA, et al: Guidelines for the initial empiric therapy of community acquired pneumonia: proceedings of an American Thoracic Society Consensus Conference. Am Rev Resp Dis 1993; 148: 1418 – 1426. 10 The British Thoracic Society: Guidelines for the management of community-acquired pneumonia in adults admitted to hospital. Br J Hosp Med 1993; 49: 346 – 350. 11 Mandell LA, Niederman MS: The Canadian Community Acquired Pneumonia Consensus Conference Group. Antimicrobial treatment of community acquired pneumonia in adults: a conference report. Can J Infect Dis 1993; 4: 25. 12 Bartlett JG, Breiman RF, Mandell LA, File TM, Jr: Community acquired pneumonia in adults: guidelines for management. Clin Infect Dis 1998; 26: 811 – 838. 13 Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM: CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16: 128 – 140. 14 Centers for Disease Control and Prevention. Preventing the spread of vancomycin

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Address for correspondence Dr M Zervos William Beaumont Hospital, 3811 West 13 Mile Road, Royal Oak, MI 48073, USA. E-mail: [email protected]

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