a Services of Infectious Diseases, b Microbiology and c Clinical Haematology, Hospital de Bellvitge, Institut Català d'Oncologia, Ciutat Sanitària i Universitària de Bellvitge, University of Barcelona, Spain
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Abstract |
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Introduction |
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Combination of an aminoglycoside with an antipseudomonal ß-lactam drug has been one of the most frequently used empirical treatments for febrile episodes in neutropenic patients with cancer. In many regimens the ß-lactam compound is ceftazidime. Recently, some institutions have reported a decline in the frequency of infections caused by Pseudomonas aeruginosa, especially among patients with solid tumours and lymphomas. This fact, along with the increase in Gram-positive bacteraemia, has prompted evaluation in empirical regimens of third-generation cephalosporins, with higher activity against Gram-positive organisms (e.g. ceftriaxone) instead of the commonly used ceftazidime.4 Recently, ceftriaxone has also been increasingly used to treat low-risk febrile patients with cancer on an outpatient basis, because of its favourable pharmacokinetic characteristics.5
The aims of the present study were to determine the prevalence of resistance to cephalosporins among VGS causing bacteraemia in neutropenic patients and to identify risk factors associated with the development of bacteraemia due to these resistant strains.
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Materials and methods |
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To identify factors associated with cephalosporinresistant viridans streptococcal bacteraemia, a comparison between cases due to cephalosporin-susceptible bacteria and those due to cephalosporin-resistant strains was carried out. For this purpose, susceptibility to cephalosporins was considered to be the same as that to ceftriaxone.
During the study period, norfloxacin was used as prophylaxis. Ceftazidime or imipenem plus amikacin were the empirical antibiotic regimens most commonly used for febrile episodes. Vancomycin was added to the initial regimen of patients in whom infection due to Gram-positive bacteria was initially suspected and also to those who had not improved after initial therapy for 48 h or who worsened before that time.
Severe mucositis was defined as the presence of multiple ulcerations covering >25% of the oral mucosa. Serious complications included the following: septic shock (defined as a systolic blood pressure of <90 mmHg and evidence of peripheral hypoperfusion) and ARDS (adult respiratory distress syndrome; defined as respiratory failure with bilateral pulmonary infiltrates and neither evidence of cardiac failure nor isolation of organisms in respiratory specimens). In the study of risk factors, prophylactic norfloxacin and prior ß-lactam therapy were considered to be present when they were given during the 2 weeks before viridans streptococcal bacteraemia developed. Attributable mortality was considered when it occurred within the first 7 days from the bacteraemia and after excluding other causes of death. Overall mortality was defined as any death occurring within 30 days from the bacteraemia.
VGS recovered from blood cultures were classified according to the taxonomy and nomenclature proposed by Bruckner & Colonna6 which includes five species/groups, namely the Streptococcus mitis, Streptococcus sanguis, Streptococcus milleri, Streptococcus salivarius and Streptococcus mutans groups. They were identified by standard methods, including colony morphology and the production of acid from trehalose, sorbitol, lactose, mannitol, sucrose, inulin, raffinose, glycerol, arabinose, maltose and sorbose. The isolates were additionally tested for reactions on aesculin agar and bileaesculin agar, growth in 6.5% NaCl broth, ammonia production from arginine, pyruvate utilization, sodium hippurate hydrolysis and hydrolysis of starch. The antimicrobial agents tested were penicillin, ceftriaxone, ceftazidime, cefepime, cefpirome, imipenem, erythromycin, ciprofloxacin and vancomycin. The MICs were determined by the microdilution method.7 Strains were classified for penicillin susceptibility according to the NCCLS criteria,8 as follows: susceptible (MIC 0.12 mg/L), intermediately resistant (MIC 0.252 mg/L) and highly resistant (MIC
4 mg/L). VGS were considered to be resistant to cephalosporins when the MIC was
2 mg/L.8 Streptococcus pneumoniae ATCC 49619 and Staphylococcus aureus ATCC 29213 were used for the quality control.
We used 2 or Fisher's exact test when appropriate for analysis of categorical variables and Student's t-test for analysis of continuous variables.
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Results |
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Table I shows the in vitro activities of nine antimicrobial agents against the 89 VGS isolated from blood cultures. Thirty-five (39%) isolates showed some degree of resistance to penicillin with an MIC range of 0.2516 mg/L, with 20 isolates (57%) being highly resistant. Rates of resistance to erythromycin, imipenem and ciprofloxacin were 36, 7 and 38%, respectively (MIC ranges 1>32 mg/L, 2 mg/L and 232 mg/L, respectively). All isolates were susceptible to vancomycin. Twenty isolates (22%) were resistant to ceftriaxone (MIC range 28 mg/L) and 47 (53%) to ceftazidime (MIC range 2>256 mg/L). Susceptibility to fourth-generation cephalosporins was tested in 35 of 89 isolates. Cefpirome was more active than cefepime; five isolates (14%) strains were resistant to cefpirome and 12 (34%) to cefepime (MIC range 24 mg/L).
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Discussion |
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According to our data, prior ß-lactam therapy appears to be a major predisposing factor for the occurrence of bacteraemia caused by resistant strains. It should be noted, however, that these resistant strains are particularly prevalent in countries with a high incidence of penicillin-resistant pneumococci, such as Spain and South Africa. Interestingly, several in vitro studies have demonstrated the potential for transfer of resistance determinants to penicillin and cephalosporins between these two streptococci species. Thus, the selection pressure of exposure to ß-lactams can promote the enrichment and spread of resistant VGS as well as resistant pneumococci.
In our experience, the outcome in patients with cephalosporin-resistant viridans streptococcal bacteraemia was not worse than that in patients with cephalosporin-susceptible viridans streptococcal bacteraemia. However, it should be pointed out that our study was not designed to address this issue. Further studies specifically analysing the clinical significance of resistance to cephalosporins are needed, both for bacteraemia and for other serious infections caused by VGS that are occasionally treated with cephalosporins, such as endocarditis or, less frequently, meningitis.
A recent study11 of the outcome of bacteraemia in neutropenic cancer patients found that six of nine patients with viridans streptococcal bacteraemia who died had been empirically treated with ceftazidime. In contrast, all patients who survived had received vancomycin in the initial antibiotic regimen. Thus, in light of our findings of a high percentage of VGS showing increased MICs to ceftazidime, we believe that, at least at institutions where penicillin-resistant VGS are prevalent, ceftazidime should not be administered empirically to neutropenic patients suspected of having viridans streptococcal bacteraemia. In recent years, some authors have advocated the use of ceftriaxone4 in order to provide a better coverage of Gram-positive infections. This antibiotic has also been increasingly used to facilitate outpatient therapy for low-risk patients with cancer.5 Therefore, our results demonstrating high rates of resistance to this agent are of great clinical relevance. Although fourth-generation cephalosporins showed a better activity than ceftazidime, a significant proportion of strains of VGS were also resistant to these agents. Imipenem was the most active of the ß-lactams, and no strain was found to be resistant to vancomycin. These findings should be considered when choosing empirical antibiotic therapy for febrile episodes in this population of patients.
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Acknowledgments |
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Notes |
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References |
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2 . Potgieter, E., Carmichael, M., Koornhof, H. J. & Chalkley, L. J. (1992). In vitro antimicrobial susceptibility of viridans streptococci isolated from blood cultures. European Journal of Clinical Microbiology and Infectious Diseases 11, 5436.[ISI][Medline]
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Received 27 April 2000; returned 24 July 2000; revised 30 August 2000; accepted 22 September 2000