High rates of resistance to cephalosporins among viridans-group streptococci causing bacteraemia in neutropenic cancer patients

Anna Marrona,*, Jordi Carratalàa, Fernando Alcaideb, Alberto Fernández-Sevillac and Francesc Gudiola

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The prevalence of resistance to cephalosporins among viridans-group streptococci causing 88 (18%) cases among 485 bacteraemias in neutropenic cancer patients was studied. Rates of resistance to ceftriaxone, ceftazidime, cefpirome and cefepime were 22, 53, 14 and 34%, respectively. Previous administration of ß-lactam therapy was the only factor significantly associated with bacteraemia due to cephalosporin-resistant strains; only 11 (16%) of 68 patients infected with cephalosporin-susceptible bacteria had received these antibiotics compared with 10 (50%) of 20 patients infected with cephalosporin-resistant bacteria (P = 0.0052).


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In recent years, viridans-group streptococci (VGS) have become a major cause of bacteraemia in neutropenic cancer patients. There has also been an increase in the severity of clinical manifestations and mortality caused by these organisms.1 Fulminant infections, adult respiratory distress syndrome (ARDS) and {alpha}-streptococcal shock syndrome are being observed in many centres. The emergence of strains resistant to multiple antibiotics in this group of organisms, which have long been considered very susceptible to penicillin (MIC <= 0.12 mg/L), constitutes another cause of great concern.2,3

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was carried out in a 1000 bed university hospital for adults, where prospective surveillance of all cases of bacteraemia in neutropenic (<500 granulocytes/mm3) patients with cancer is performed regularly. For the purposes of the present study, we examined all episodes of viridans streptococcal bacteraemia in neutropenic patients with cancer documented from January 1986 to December 1996. The diagnosis of viridans streptococcal bacteraemia was established by the presence of two or more sets of blood cultures positive for VGS. Cases in which a single blood culture yielded these bacteria were included only when signs of septicaemia were present.

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 bile–aesculin 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 0.25–2 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 {chi}2 or Fisher's exact test when appropriate for analysis of categorical variables and Student's t-test for analysis of continuous variables.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Over the study period, 485 episodes of bacteraemia were documented among neutropenic cancer patients. Eighty-eight (18%) of these episodes were caused by VGS. Strains were identified as Streptococcus mitis group (n = 72), Streptococcus salivarius group (n = 7), Streptococcus sanguis group (n = 5), Streptococcus milleri group (n = 3) and Streptococcus mutans group (n = 2). One episode was caused by S. mitis and S. salivarius groups concomitantly.

Table IGo 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 0.25–16 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 2–32 mg/L, respectively). All isolates were susceptible to vancomycin. Twenty isolates (22%) were resistant to ceftriaxone (MIC range 2–8 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 2–4 mg/L).


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Table I. In vitro activities of nine antimicrobial agents against 89 strains of VGS isolated from blood of neutropenic patients with cancer
 
A comparison of the clinical findings in patients with cephalosporin-susceptible and cephalosporin-resistant viridans streptococcal bacteraemia is shown in Table IIGo. Prior administration of ß-lactam antibiotics was the only factor significantly associated with cephalosporin-resistant cases; 11 (16%) of 68 patients with cephalosporin-susceptible bacteraemia had received ß-lactam antibiotics as compared with 10 (50%) of 20 patients with cephalosporin-resistant bacteraemia (P = 0.0052). Ceftazidime was the prior ß- lactam most frequently given to patients with cephalosporin-resistant bacteraemia (eight of 10 patients). In fact, four patients developed breakthrough bacteraemia due to resistant strains while receiving ceftazidime. The other ß-lactams given to patients with bacteraemia due to cephalosporin-resistant isolates were imipenem in two cases (one patient received both imipenem and ceftazidime) and amoxycillin–clavulanate in one case. In patients with cephalosporin-susceptible bacteraemia, the ß-lactams used were ceftazidime in nine cases and imipenem in two cases.


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Table II. Comparison between cephalosporin-susceptible and cephalosporin-resistant VGS bacteraemia in 88 neutropenic patients with cancera
 
Ten of the 88 patients (11%) developed serious complications: ARDS plus septic shock in five patients, ARDS in three patients and septic shock in two patients. The VGS isolated from five of these 10 patients were resistant to ceftazidime (MIC range 2–>32 mg/L), with three of them also being resistant to ceftriaxone (MICs 2–8 mg/L) and cefepime (MIC range 2–4 mg/L). Attributable mortality was 9% (eight of 88 patients) and overall mortality was 22% (19 of 88 patients). The comparative study did not show significant differences between cephalosporin-susceptible and cephalosporin-resistant bacteraemic episodes regarding the development of serious complications or in mortality rates.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Over recent years, penicillin-resistant VGS have been increasingly isolated worldwide. In South Africa, 38% of strains isolated from blood cultures between 1988 and 1991 were found to be resistant to penicillin.2 A recent study conducted in the USA, which included mostly nonneutropenic patients, showed that 56% of VGS recovered from blood cultures were resistant to penicillin.3 In addition, some studies dealing with neutropenic patients with cancer9 have also shown an increasing incidence of viridans streptococcal bacteraemia caused by penicillin-resistant strains. Nevertheless, experiences regarding the activities of cephalosporins against VGS isolated from the blood of neutropenic cancer patients are limited.10 In the present study, a substantial proportion of isolates were resistant to ceftriaxone. Importantly, ceftazidime was found to be the least active of the cephalosporins tested. Regarding the activities of the fourth-generation cephalosporins, we found that the rate of resistance to cefepime was higher than that to cefpirome.

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.


    Acknowledgments
 
This work was supported by a grant from Fondo de Investigaciones Sanitarias (93/1081, 93/1196) and Fundació August Pi i Sunyer.


    Notes
 
* Correspondence address. Feixa Llarga s/n, 08907 l'Hospitalet, Barcelona, Spain. Tel: +34-93-3357011 (ext. 2487); Fax: +34-93-2607637; E-mail: jcarratala{at}csub.scs.es Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Elting, L. S., Bodey, G. P. & Keefe, B. H. (1992). Septicemia and shock syndrome due to viridans streptococci: a case–control study of predisposing factors. Clinical Infectious Diseases 14, 1201–7.[ISI][Medline]

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, 543–6.[ISI][Medline]

3 . Doern, G. V., Ferraro, M. J., Brueggemann, A. B. & Ruoff, K. L. (1996). Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrobial Agents and Chemotherapy 40, 891–4.[Abstract]

4 . Anonymous. (1993). Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Annals of Internal Medicine 119, 584–93.

5 . Karthaus, M., Wolf, H. H., Kampfe, D., Egerer, G., Ritter, J., Peters, G. et al. (1998). Ceftriaxone monotherapy in the treatment of low-risk febrile neutropenia. Chemotherapy 44, 343–54.[ISI][Medline]

6 . Bruckner, D. A. & Colonna, P. (1997). Nomenclature for aerobic and facultative bacteria. Clinical Infectious Diseases 25, 1–10.[ISI][Medline]

7 . National Committee for Clinical Laboratory Standards. (1993). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Third Edition: Approved Standard M7-A3. NCCLS, Villanova, PA.

8 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth Edition: Approved Standard M100-S7/M7-A4. NCCLS, Villanova, PA.

9 . Carratalà, J., Alcaide, F., Fernández-Sevilla, A., Corbella, X., Liñares, J. & Gudiol, F. (1995). Bacteremia due to viridans streptococci that are highly resistant to penicillin: increase among neutropenic patients with cancer. Clinical Infectious Diseases 20, 1169–73.[ISI][Medline]

10 . Pfaller, M. A., Marshall, S. A. & Jones, R. N. (1997). In vitro activity of cefepime and ceftazidime against 197 nosocomial blood-stream isolates of streptococci: a multicenter sample. Diagnostic Microbiology and Infectious Disease 29, 273–6.[ISI][Medline]

11 . Elting, L. S., Rubenstein, E. B., Rolston, K. V. & Bodey, G. P. (1997). Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clinical Infectious Diseases 25, 247–59.[ISI][Medline]

Received 27 April 2000; returned 24 July 2000; revised 30 August 2000; accepted 22 September 2000