Cefepime versus cefotaxime for empirical treatment of bacterial pneumonia in HIV-infected patients: an open, randomized trial

E. Corderoa,*, E. Bouzab, I. Ruizc and J. Pachona

a Infectious Diseases Services, Hospitales Universitarios Virgen del Rocío, Sevilla; b Microbiology and Infectious Diseases Service, Hospital Gregorio Marañón, Madrid; c Infectious Diseases Service, Hospital Valle d'Hebron, Barcelona, Spain


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
An open, randomized, multicentre clinical trial was conducted to compare the efficacy and safety of cefepime 2 g iv bd (2 g tds daily in cases of Pseudomonas aeruginosa pneumonia) with cefotaxime 2 g iv tds, in the empirical treatment of bacterial pneumonia in HIV-infected patients. The primary end-point was effectiveness after 3–5 days of treatment, taking success to be when the study drug was continued during this period of time. Clinical and bacteriological responses at end of treatment (EOT) were also evaluated. Analyses of the intention-to-treat population (n = 160) and the as-per-protocol groups (n = 150) were carried out. Treatment groups were comparable with regard to sex, age, HIV status and degree of severity of pneumonia. The primary end-point for cefepime was considered successful for the intention-to-treat and as-per-protocol groups in 85.7% and 93.5% of cases, respectively, and for cefotaxime, in 77.6% and 80.8% of cases, respectively (P = 0.22 and P = 0.02). In the as-per-protocol group, cefotaxime treatment was independently related to failure at the primary end-point. A satisfactory clinical response in the intention-to-treat population was observed in 83.3% of cefepime and 82.9% of cefotaxime patients. Bacteriological cure was obtained in 100% of evaluable cefepime and 93.4% of evaluable cefotaxime patients at EOT. Safety of the study drugs was comparable in both treatment groups. Cefepime 2 g iv bd was at least as effective and as well tolerated as cefotaxime 2 g iv tds in the treatment of bacterial pneumonia in HIV-infected patients.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Bacterial pneumonia is a common cause of morbidity in HIV-infected patients, with an incidence of 19.3–290 per 1000 patients per year.13 Despite a marked reduction in incidence after the introduction of highly active antiretroviral therapy (HAART), bacterial pneumonia continues to be the primary cause of hospital admission4 and a major cause of morbidity and mortality among HIV-infected patients.5

Streptococcus pneumoniae is the main cause of bacterial pneumonia in HIV-infected patients; however, aetiology is very varied, with a considerable incidence of Gramnegative bacilli (24–44%).1,2,6 In the last few years, an increased frequency of Pseudomonas aeruginosa as a cause of community-acquired pneumonia has been reported in HIV-infected patients.6,7

Antimicrobial therapy of bacterial pneumonia must be prompt and adequate, but in HIV-infected patients there are no guidelines for the empirical treatment of bacterial pneumonia. On the basis of retrospective studies, the use of second- or third-generation cephalosporins or co-trimoxazole has been proposed,8,9 but clinical trials are lacking.

Cefepime is a fourth-generation cephalosporin with a broad spectrum of activity, including Gram-positive and Gram-negative aerobes.1012 Its in vitro activity against S. pneumoniae is better than that of ceftazidime and similar to that of cefotaxime.13 It also has good activity against methicillin-susceptible Staphylococcus aureus, Enterobacteriaceae, Haemophilus influenzae and P. aeruginosa.10,1416 Cefotaxime has been widely used in the treatment of bacterial pneumonia and has good activity against the microorganisms most frequently involved in HIV-infected bacterial pneumonia (S. pneumoniae, H. influenzae and S. aureus).17

The purpose of this study was to evaluate the effectiveness and tolerability of cefepime in the treatment of bacterial pneumonia in HIV-infected patients. The hypothesis tested was that cefepime was at least as effective and as well tolerated as cefotaxime in the empirical treatment of bacterial pneumonia in HIV-infected patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Study design

This was an open, multicentre, randomized and comparative trial of cefepime 2 g iv bd and cefotaxime 2 g iv tds. Randomization was computer generated (1:1) for the reception of cefepime or cefotaxime and then distributed within each study centre. The duration of both therapies was at the discretion of the researcher but should have lasted for 5 days, or at least 48 h after fever subsided. A change to oral therapy was allowed if clinical signs and symptoms of pneumonia improved. When the microorganism isolated was P. aeruginosa, the cefepime dosage was raised to 2 g iv tds.

The protocol was approved by the local ethics committee and the study was conducted in accordance with the Good Clinical Practice Guidelines of the European Community and Declaration of Helsinki. Written informed consent was obtained from all patients.

Each centre was provided with study medication by the sponsor of this study (Bristol-Myers Squibb, Madrid, Spain).

Patients

Patients were enrolled in the study if all of the following criteria were fulfilled: age >=18 years; HIV infection; a negative pregnancy test for women of child-bearing age; clinical evidence of suspected or confirmed community- or hospital-acquired bacterial pneumonia manifested by the presence of a new radiological infiltrate, body temperature >38°C and one or more of the following conditions: chest pain, cough, bronchial rales. The degree of severity of the bacterial pneumonia and the prognostic classification were determined using the criteria of the American Thoracic Society for community-acquired pneumonia18 and a well known Prognostic Score Index.19 The pneumonia was considered to be community-acquired if symptoms occurred in a patient who had not been hospitalized in the previous 7 days.

Exclusion criteria were: previous enrolment in this study; hypersensitivity to cephalosporins; pregnancy or breastfeeding; serum creatinine of >2 mg/dL; previous treatment lasting longer than 24 h with an antimicrobial potentially appropriate for bacterial pneumonia, unless it was non-efficacious; life expectancy <2 months.

Discontinuation criteria were: any serious adverse event that precluded the continuation of the study drug; any concomitant pathology requiring therapy incompatible with the study drugs; resistance of the baseline pathogen to the assigned antimicrobial regime; the discretion of the patient or researcher.

Empirical efficacy

Since this is an empirical study, the primary end-point was efficacy after 3–5 days of treatment, taking success to be the continuation of the study drug during this period of time. Failure was defined for any of the following situations: the isolation of bacteria resistant to the study drug, the addition of one or more antibiotics and/or discontinuation of the assigned therapy because of persistence or worsening of signs and symptoms. An analysis was performed on the intention-to-treat population, including all patients who received at least one dose of the study drug. In this analysis, patients who withdrew from the trial at their own discretion or those with a final diagnosis other than bacterial pneumonia were considered failures. An analysis of the as-per-protocol group was also carried out.

Secondary variables were clinical and bacteriological efficacy at end of treatment (EOT) and safety.

Clinical evaluation

Clinical efficacy at EOT was analysed using the following definitions. (i) Cure: resolution of all symptoms and signs of the pneumonia. (ii) Improvement: improvement of signs and symptoms without complete radiological resolution. There should have been no radiological progression. (iii) Failure: all pneumonia-related signs and symptoms and radiological findings remained unchanged or worsened; the development of new pulmonary findings consistent with an active infection; death attributed to pneumonia; discontinuation of study treatment because of adverse events. (iv) Indeterminate: other circumstances different from cure, improvement or failure.

Bacteriological evaluation

Two sets of blood cultures (aerobic and anaerobic) were taken from 142 patients. Sputum samples were obtained when the patients were able to expectorate. Sputa were considered acceptable if they contained >25 polymorphonuclear cells and <10 epithelial cells per low-power field. The microbiological samples were processed during the 48 h before starting therapy, at days 3–5 of treatment, at EOT and at follow-up (if considered clinically necessary and feasible). Fibreoptic bronchoscopy and pulmonary needle aspiration were indicated by the clinician in charge of the patient in cases with no diagnosis by non-invasive techniques and/or absence of improvement with empirical treatment. The susceptibility of the microorganisms isolated was determined by Etest in a central laboratory. The NCCLS breakpoints for susceptibility with dilution methods were employed.20 Serological testing for Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia spp. and Coxiella burnetii was carried out initially and again after 1 month; for the diagnosis, a four-fold increase in the titre of antibodies between the acute and convalescent sera was required. The S. pneumoniae antigen was determined at baseline in serum and urine by counter-immunoelectrophoresis with polyvalent pneumococcal serum from the Copenhagen Staten Serum Institute.21

Bacteriological efficacy was determined at EOT and was defined under one of six categories. (i) Eradication: baseline pathogen eradicated during or at EOT. (ii) Presumed eradication: the patient had improved clinically but a follow-up culture could not be obtained. (iii) Persistence: baseline pathogen still present. (iv) Re-infection: emergence of the baseline pathogen after two consecutive negative cultures. (v) Superinfection: new pathogen emerged during treatment. (vi) Indeterminate: not possible to classify microbiological response (due to death, lack of follow-up).

Safety

All patients who received at least one dose of the study drug were evaluated for safety. Adverse events were classified as severe in the presence of any of the following criteria: death or risk of death; permanent incapacity; required or prolonged hospitalization; cancer; congenital abnormalities; overdose. The relationship to treatment was recorded as possibly related, probably related, certainly related and certainly not related.

Statistical analysis

Assuming a success rate of 80% in both groups of treatment, a minimum of 76 patients per treatment group was required to be able to test any difference in success >=15%, with a two-sided {alpha} error of 0.05 and a ß error of 0.20.22 We used the Fisher's exact and {chi}2 tests to compare the effectiveness and safety of the study regimes. A logistic regression analysis was performed to determine the factors independently associated with failure of treatment.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
From April 1996 to May 1997, 160 patients were enrolled and randomized in 18 Spanish centres (84 in the cefepime group and 76 in the cefotaxime group).

All patients were evaluated at the primary end-point (after 3–5 days of treatment), and clinical efficacy at EOT in the intention-to-treat population.

In the analysis of the as-per-protocol group, 10 patients (6.2%) were excluded from the primary end-point efficacy analysis, six of them because of a final diagnosis other than bacterial pneumonia, and in four cases at the discretion of the patient. In the clinical efficacy analysis, one additional patient was excluded at his own discretion at day 5. Eight patients belonged to the cefepime group and three to the cefotaxime group (Table 1Go).


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Table 1. Evaluable patients at each phase of the study
 
Pneumonia was community acquired in all cases (98.7%), except two (one in each treatment group) which were hospital acquired.

The cefepime and cefotaxime groups were similar with respect to age, sex, toxic habits, plasma HIV RNA, CD4+ count, HIV status23 and Karnofsky score. The mean age was 35.5 ± 7.8 years and 71% were male. The majority of patients had a Karnofsky score >=80 (84.3%). The mean CD4+ count was 205 ± 197.4 cells/µL, 59.3% of patients had <200 cells/µL, and 68.7% of patients had been previously diagnosed with AIDS.23 Mean plasma HIV RNA was 25804 copies/mL. The proportion of patients with plasma HIV RNA below detectable levels was similar in both groups (15.6% in the cefepime group and 12.3% in the cefotaxime group). Underlying or concomitant illnesses were reported in 131 cases (81.8%), hepatobiliary diseases (56.2%) being the most common. Alcohol abuse was reported in 30 patients (18.7%), 103 patients (64.3%) were illicit drug users and 131 (81.8%) tobacco smokers. A diagnosis of bacterial pneumonia in the year previous to enrolment was made in 33% of patients in the cefepime group and 18% in the cefotaxime group (P = 0.04). Pre-treatment with systemic antibiotics was reported in 90 patients (56.2%), with no differences between study groups (56% in the cefepime group and 55% in the cefotaxime group). Most of these cases, 84.6%, corresponded to a single dose of antibiotics in the emergency room before entering the protocol. The antimicrobial agents employed most frequently were third-generation cephalosporins (51.1%), followed by trimethoprim–sulfamethoxazole (34.4%) and macrolides (23.3%).

The main symptoms are summarized in Table 2Go and were similar in both cefepime and cefotaxime groups. There were no differences between the two groups of treatment in terms of clinical manifestation, radiological findings or severity (Table 2Go).


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Table 2. Clinical and radiological findings
 
The length of study of drug administration was 7 days in the cefepime group and 7.7 days in the cefotaxime group (P = 0.59). Neither the total duration of the antimicrobial therapy (iv plus oral, 12.1 ± 5.6 days versus 12.7 ± 5.6 days, P = 0.45) nor the type of continuation oral therapy differed between groups. The most common antimicrobials employed as continuation oral therapy were cefuroxime axetil (34 patients treated with cefepime and 22 patients with cefotaxime), co-amoxiclav (eight patients in each treatment group), amoxicillin (three patients treated with cefepime and four with cefotaxime) and macrolides (three patients in the cefepime group and two in the cefotaxime one). The length of hospital stay for the cefepime group was 11.1 ± 6.8 days, and 14.4 ± 11.8 days for the cefotaxime group (P = 0.2).

The initial antibiotic regime was maintained throughout the study (the first 3–5 days) in 72 cefepime (85.7%) and 59 cefotaxime patients (77.6%, P = 0.22). Referring to the evaluable population of the as-per-protocol group (150 patients), 72 of the 77 patients (93.5%) in the cefepime group and 59 of the 73 patients (80.8%) in the cefotaxime group remained on the study drug after 3–5 days of treatment [P = 0.02, odds ratio (OR) 3.42, 95% confidence interval (CI) 1.22–9.55]. The reasons for failure are detailed in Table 3Go.


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Table 3. Primary end-point and clinical response analyses
 
At EOT (Table 3Go), 83.3% of patients in the cefepime group and 82.9% of patients receiving cefotaxime in the intention-to-treat population had a satisfactory clinical response (P = 0.76, OR 1.22, 95% CI 0.7–2.15). In the as-per-protocol analysis for clinical efficacy (149 patients), 92.1% of patients were cured or improved in the cefepime and 86.3% in the cefotaxime group (P = 0.39, OR 1.85, 95% CI 0.64–5.53). Radiological progression after 3–5 days occurred in 10 patients, four in the cefepime group and six in the cefotaxime group (P = 0.3).

A multivariate analysis was carried out to determine whether the type of antimicrobial agent was an unsatisfactorily related independent risk factor. In this model the variables introduced were CD4+ cells/µL, HIV RNA viral load, severity of the pneumonia, previous respiratory infection, age, sex and group of treatment. Cefotaxime treatment was the only variable independently related to failure at the primary end-point (P = 0.025, OR 3.42, 95% CI 1.16–10.04). When the end-point was clinical efficacy, none of these variables showed a significant relationship with clinical failure.

An aetiological diagnosis was obtained in 85 patients, in 59 by isolating a potentially significant pathogen, and in the remaining 26 by indirect methods (Table 4Go). The most common agents were S. pneumoniae, H. influenzae and S. aureus. The distribution of pathogens between treatment groups was similar. Among the microorganisms isolated, two strains were resistant to the antimicrobial assigned, one of them to cefepime: an isolate of S. pneumoniae (MIC 5 mg/L), from a patient with clinical cure without changing the antimicrobial, and one to cefotaxime: an isolate of P. aeruginosa (MIC > 90 mg/L), from a patient with clinical failure but with improvement after changing to imipenem plus amikacin.


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Table 4. Aetiology of bacterial pneumonia
 
The aetiology of two cases of hospital-acquired pneumonia was unknown. Eleven patients had atypical pathogens: eight with clinical cure and three with clinical failure; the failures occurred in both of the patients with Chlamydia pneumoniae and in the patient with L. pneumophila treated with cefotaxime. The pneumonia was bacteraemic in 21.8% of cases.

Bacteriological eradication was observed in 100% of the 29 patients from the cefepime group and in 93.4% of the 30 patients from the cefotaxime group. The non-eradicated microorganisms were S. pneumoniae (n = 1) and P. aeruginosa (n = 1). A superinfection occurred in eight patients, four in each treatment group: in the cefotaxime group, the pathogens were Acinetobacter baumannii, Staphylococcus epidermidis, Candida albicans and Clostridium difficile; in the cefepime group, the pathogens were Mycobacterium kansasii, Pneumocystis carinii, Leishmania spp. and P. aeruginosa.

Safety was evaluated in the intention-to-treat population. Fifty patients (31.2%), 25 in each study group, reported a total of 70 adverse events, of which 14 were considered possibly, probably or certainly related to the study drugs (Table 5Go). There were no significant differences in the type of adverse effect between the groups of antibiotics. The most commonly affected system of the body was the digestive system.


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Table 5. Adverse events
 
Only one severe event in each study group was possibly related to the study drug. The study antibiotic was discontinued in four patients due to adverse events: three (3.9%) in the cefotaxime group and one (1.2%) in the cefepime group. There were three deaths during the study and all were related to the pneumonia: one patient treated with cefepime and two with cefotaxime; in only one case, a patient treated with cefotaxime, was the aetiology known (P. aeruginosa).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
The patient population in this study was well matched in terms of basal characteristics, HIV status and microorganisms isolated in both antibiotic groups. The severity of the bacterial pneumonia was also similar in both groups. The results indicate that cefepime was at least as effective as cefotaxime in the empirical treatment of bacterial pneumonia in HIV-infected patients. The clinical cure rates at EOT were 83.3% for cefepime and 82.9% for cefotaxime in the intention-to-treat population, and 92% and 86%, respectively, for the as-per-protocol group. However, although there were no differences in the intention-to-treat population, the as-per-protocol analysis showed that cefotaxime was independently related to failure for the primary end-point.

To our knowledge there are no clinical trials for the empirical treatment of bacterial pneumonia in HIV-infected patients. However, in trials carried out on immunocompetent patients, the cure rates for cefotaxime or cefepime were similar to those obtained in this study. Clinical success rates of 56–94.8% have been reported for immunocompetent patients with community-acquired pneumonia treated with cefotaxime2426 and 73–91% for those treated with cefepime.25,2729

It should be noted that in the as-per-protocol group there were more non-evaluable patients after treatment with cefepime than after treatment with cefotaxime; however, this was not statistically significant and no reason could be found for this effect. This proportion was low (<10%), especially when we consider that most of the patients withdrew at their own discretion and that the population included 64.7% active illicit drug users.

The aetiology of pneumonia was similar to that found in previous series, S. pneumoniae and H. influenzae being the most frequently isolated pathogens. The proportion of P. aeruginosa was lower than in other studies,6,7 probably related to the low proportion of patients with <50 CD4+ cells/µL (25%), a factor related to the occurrence of P. aeruginosa pneumonia in HIV-infected patients.30

Bacteriological response was good in both groups, with no differences between them, at 100% of the cefepime group and 93.4% of those assigned to cefotaxime therapy. One patient with documented P. aeruginosa pneumonia failed to improve after 6 days of cefotaxime therapy (MIC > 32 mg/L) but showed a good response to imipenem and amikacin. A patient with bacteraemic pneumococcal pneumonia remained bacteraemic after 11 days of therapy with cefotaxime (MIC 0.5 mg/L), but responded after changing to vancomycin, amikacin plus piperacillin.

Cefepime and cefotaxime were well tolerated and the two drugs were comparable in this respect. They were withdrawn because of adverse effects in only four cases.

We conclude that cefepime was at least as effective and as well tolerated as cefotaxime in the treatment of bacterial pneumonia in HIV-infected patients.


    Acknowledgements
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was supported by a research grant from Bristol-Myers Squibb.


    Notes
 
* Corresponding author. Tel/Fax: +34-95-501-2377; E-mail: mcordero{at}cica.es Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Received 30 March 2001; returned 12 June 2001; revised 30 July 2001; accepted 6 August 2001





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