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
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Abstract |
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Introduction |
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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 (2444%).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.
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Patients and methods |
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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 35 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 35 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
error of 0.05 and a ß error of 0.20.22 We used the Fisher's exact and
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.
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Results |
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All patients were evaluated at the primary end-point (after 35 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 1).
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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 trimethoprimsulfamethoxazole (34.4%) and macrolides (23.3%).
The main symptoms are summarized in Table 2 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 2
).
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The initial antibiotic regime was maintained throughout the study (the first 35 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 35 days of treatment [P = 0.02, odds ratio (OR) 3.42, 95% confidence interval (CI) 1.229.55]. The reasons for failure are detailed in Table 3.
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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 1.1610.04). 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 4). 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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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 5). 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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Discussion |
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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 5694.8% have been reported for immunocompetent patients with community-acquired pneumonia treated with cefotaxime2426 and 7391% 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.
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Acknowledgements |
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Notes |
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References |
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Received 30 March 2001; returned 12 June 2001; revised 30 July 2001; accepted 6 August 2001