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Epidemiology and Risk Factors for Gram-Positive Coccal Infections in Neutropenia: Toward a More Targeted Antibiotic Strategy

  1. Catherine Cordonnier1,
  2. Agnès Buzyn3,
  3. Guy Leverger4,
  4. Raoul Herbrecht5,
  5. Mathilde Hunault6,
  6. Roland Leclercq6,
  7. Sylvie Bastuji-Garin2, and
  8. Club de Réflexion sur les Infections en Onco-Hématologie
  1. 1Hematology Department, University Paris XII, Henri Mondor Hospital, Créteil
  2. 2Public Health Department, University Paris XII, Henri Mondor Hospital, Créteil
  3. 3Hematology Department, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris
  4. 4Pediatrics Department, Trousseau Hospital, Assistance Publique—Hôpitaux de Paris, Paris
  5. 5Hautepierre Hospital, Strasbourg
  6. 6Hematology Department, University Hospital, Angers
  7. 7Microbiology Department, University Hospital, Caen, France
  1. Reprints or correspondence: Dr. Catherine Cordonnier, Hematology Dept., Henri Mondor Hospital, 94000 Créteil, France (carlcord{at}club-internet.fr).
 
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Abstract

The objective of this study was to evaluate the risk of acquiring gram-positive coccal infections in febrile neutropenic patients and to develop risk indexes for gram-positive and streptococcal infections. This prospective, multicenter study included 513 patients. The prevalence of gram-positive coccal infections was 21% (14% were staphylococcal infections and 7.8% were streptococcal infections). The mortality rate during the month after study enrollment was 5%. On multivariate analysis, the occurrence of gram-positive coccal infections was significantly associated with receipt of high-dose cytarabine therapy, proton pump inhibitors, and gut decontamination with colimycin without glycopeptides and presence of chills. Staphylococcal infection was significantly associated with use of nonabsorbable colimycin, and streptococcal infection was associated with diarrhea, use of nonabsorbable antifungals, receipt of high-dose cytarabine, and gut decontamination with colimycin. The relative risks for streptococcal infection were 2.9, 13.2, and 20.7 in the presence of 1, 2, and ⩾3 parameters, respectively. Risk factors for staphylococcal and streptococcal infections differ among neutropenic patients. A simple scoring system for predicting streptococcal infection is proposed.

The increasing mortality rate for patients with febrile neutropenia due to gram-positive coccal infections (especially streptococcal infections) has been attributed to receipt of quinolone prophylaxis, receipt of high-dose cytarabine treatment, and the presence of central venous catheters [1–3]. The current challenge for physicians is to choose appropriate antibiotics to protect against septic shock and acute respiratory distress syndrome due to streptococci while avoiding an increase in the prevalence of antibiotic-resistant organisms [4]. β-Lactams do not all have adequate activity against gram-positive organisms: cefotaxime and ceftriaxone are effective against β-lactam—susceptible strains, but they have limited antipseudomonal activity, and ceftazidime, which is commonly used to treat patients with Pseudomonas aeruginosa infection, may not be the best choice to treat streptococcal bacteremia [5]. The routine use of glycopeptides remains controversial [6, 7]. Coagulase-negative staphylococci are the most common cause of gram-positive bacteremia [8–11], but staphylococcal bacteremia results in a low mortality rate, whereas oral streptococci, which are responsible for up to 39% of infections in neutropenic hosts [12], have been associated with mortality rates of 4%–22% [1, 13]. We conducted this prospective study to determine the prevalence of and risk factors for gram-positive coccal infection in febrile neutropenic patients and to establish a risk index to aid physicians in their choice of first-line antibiotics for the treatment of individual patients.

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Patients and Methods

Patients. All consecutive patients who had a first episode of fever while they had neutropenia were prospectively enrolled at 36 French hematology centers during a 2-month period (table 1). Fever was defined as a temperature of ⩾38.3°C once or ⩾38°C twice within 8 h. Neutropenia was defined as a granulocyte count of <500 cells/μL or as a granulocyte count that was expected to decrease to <500 cells/μL ⩽48 h after study enrollment because of recent receipt of chemotherapy. Patients could be included in the study only once. Patients with solid tumors were excluded, except for those who had neutropenia after they underwent autologous stem cell transplantation.

Table 1
Table 1

Characteristics of 513 hospitalized patients with neutropenia and fever who were investigated for assessment of risk factors for gram-positive coccal infection.

Of the 532 enrolled patients, 14 did not meet the inclusion criteria and 5 had missing data. Of the remaining 513 patients, 291 were male and 222 were female. The mean age (±SD) was 40.8 ± 21.7 years; 92 (18%) of the patients were children (age, <15 years). The number of patients included per center was 1–48 (median, 11).

Neutropenia was most often due to chemotherapy without stem cell transplantation. At the time of study enrollment, two-thirds of the patients had granulocyte counts of <100 cells/μL, 81% had a central venous catheter in place, and 77% were already hospitalized. All patients had blood samples obtained for ⩾2 cultures for aerobic and anaerobic organisms before they began receiving antibiotics. In accordance with international guidelines for first-line treatment [14], 91% of the patients received β-lactams, 66% received aminoglycosides, and 31% received glycopeptides, usually vancomycin.

Data collection. Data that were collected at study enrollment included the following: hematological diagnosis and status, cause of neutropenia, conditioning regimen for transplantation (when applicable), chemotherapy received during the month before enrollment, all anti-infective drugs taken ⩽7 days before study enrollment (including drugs used for gut decontamination, antifungal agents, and growth factors), administration of antiulcer and antacid drugs, location during the week before study enrollment (laminar air-flow room, single room, ⩾2-bed room, or outpatient status), and site of the intravenous catheter (central or peripheral). Clinical data included information regarding the presence of infection focus and organ failure. Day 1 was the day of study enrollment. On day 30 after enrollment, the patient's clinical status was recorded or the cause of death was determined by the investigator at each center, and the findings were independently reviewed by 2 of the principal investigators (C.C., A.B, or G.L.). Decreased susceptibility of streptococci to penicillin and methicillin-resistant staphylococci were defined according to the recommendations of the Comité Français de l'Antibiogramme [15].

Classification of patients and definitions. For each febrile neutropenic episode, patients were classified as having fever of unknown origin, clinically documented infection, or microbiologically documented infection, according to the definitions of the Immunocompromised Host Society [14]. “High-dose cytarabine” was defined as a dose of ⩾1.5 g/m 2. Mucositis was graded according to the World Health Organization score. Dental status at enrollment was graded as follows: 1, no visible teeth; 2, teeth without dental lesions or prior work; 3, presence of crowns, bridges, or implants without lesions; and 4, cavities, broken teeth, or exposed roots.

Statistical analysis. Prevalences of gram-positive coccal, streptococcal, and staphylococcal infections were computed by use of the total number of included patients as the denominator. Ninety-five percent CIs were also calculated.

To identify risk factors, the baseline characteristics of patients who had gram-positive coccal infections (streptococcal and staphylococcal infections), including those who had concomitant gram-negative infections, were compared with the baseline characteristics of patients who did not have gram-positive coccal infections. ORs with 95% CIs were calculated separately for each parameter by means of unconditional logistic regression models. Age (adulthood or childhood) was included in all of the models. Variables with a P value of ⩽.15 on univariate analysis were then entered into multivariate logistic models [16]. Multiple 2 × 2 analyses were used to assess interaction and confusion. When an interaction was found, a composite variable was built. The same analyses were done to identify risk factors for streptococcal infection and for staphylococcal infection.

Independent risk factors determined on multivariate analysis (P ⩽.05) were used to create a gram-positive risk index (GPRI) and a streptococcal infection risk index (SRI) by adding the number of factors for each patient. The GPRI was then compared between patients with and patients without gram-positive coccal infection, and the SRI was compared between patients with and patients without streptococcal infection. To determine the risk of infection, the relative risk (estimated with the OR) for gram-positive coccal infection and the relative risk for streptococcal infection were calculated according to the number of factors present at study enrollment. A formal goodness-of-fit test was used to evaluate the calibration of both models [17], and the area under the receiver operating characteristic (ROC) curve was calculated to evaluate the discriminatory power of the indexes [18]. To assess the predictive value of the GPRI and SRI, we compared the scores of patients who had gram-negative infection with the scores of patients who did not have gram-negative infection; patients who had both gram-positive and gram-negative infections were excluded. For the SRI, the scores of patients with and patients without staphylococcal infection were also compared; patients who had both streptococcal and gram-negative or streptococcal and staphylococcal infections were excluded.

Data are presented as mean ± SD or as proportions, as appropriate. All significance tests were 2-tailed. P ⩽.05 was considered to be statistically significant. Data were analyzed with use of BMDP software (University of California, Berkeley).

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Results

Causes of fever, prevalence of infection, and mortality rate. The causes of fever, the prevalence of infection, and the mortality rate are shown in table 1. Of the 168 microbiologically documented infections, 147 (87.5%) were documented by blood culture. The prevalence of streptococcal infection was 7.8% (95% CI, 5.5%–10.1%). Of the 24 isolates of oral (viridans) streptococci isolates (Streptococcus mitis and others), 13 (54%) were susceptible to penicillin, 7 (29%) had decreased susceptibility to penicillin, 1 (4%) was resistant to penicillin, and 3 had unknown resistance profiles. Four patients had both streptococcal and staphylococcal infections, and 1 had both streptococcal and gram-negative infections. The prevalence of staphylococcal infection was 14.0% (95% CI, 11.0%–17.0%). Of the 53 isolates of coagulase-negative staphylococci, susceptibility to methicillin was known for 47; of these, 27 (57%) were resistant to methicillin. Of 14 Staphylococcus aureus isolates, methicillin susceptibility status was known for 12; of these 12 isolates, 4 were methicillin resistant. Five patients had both staphylococcal and gram-negative infections. The overall prevalence of gram-positive coccal infection was 21.0% (95% CI, 17.5%–24.6%). Among these patients, 6 also had gram-negative infections. The overall prevalence of gram-negative infections was 10.7% (95% CI, 8.0%–13.4%).

The overall mortality rate during the first 30 days of the study was 5%. The mortality rates were 3% for patients with fever of unknown origin (9 of 305 patients), 15% for those with clinically documented infection (6 of 40 patients), and 8% for those with microbiologically documented infection (13 of 168 patients). Death was not directly related to the initial episode in any of the patients who had fever of unknown origin, but it was related to the initial episode in 3 (7.5%) of those who had clinically documented infection and in 6 (4%) of those who had microbiologically documented infections (2 patients with streptococcal infections and 1 patient each infected P. aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Candida species). Of the 3 patients whose deaths were attributed to streptococcal infection alone or were associated with another contributing factor, 1 was infected with penicillin-susceptible Streptococcus pneumoniae, 1 was infected with an oral Streptococcus species, and 1 was infected with an untyped streptococcal strain. These 3 patients had all been treated with first-line β-lactams that are active against streptococci (1 patient each was treated with piperacillin, ticarcillin plus clavulanic acid, and cefpirome), and 2 of these patients had also received vancomycin. None of the patients with staphylococcal infections died as a result of the initial episode. Of the 14 deaths that were considered to have been due to an infectious cause, 9 (2%) were related to the initial episode alone (n = 7) or were associated with a contributory cause (n = 2). No relationship was found between the number of positive blood culture results and the risk of death.

Factors associated with gram-positive coccal infections. On univariate analysis, previous hospitalization in a laminar air-flow room, treatment with high-dose cytarabine, oral nonabsorbable antifungals, or oral colimycin without glycopeptide, and chills, mucositis, and diarrhea at study enrollment were significantly associated with gram-positive coccal infection (table 2). Quinolone use (5% among gram-positive coccal infections vs. 6% among others), severe neutropenia (71% vs. 69%), underlying disease, dental status, presence of cutaneous lesions (7% vs. 8%), and bronchopulmonary focus (6% vs. 10%) did not influence the occurrence of gram-positive coccal infection. On multivariate analysis, only administration of high-dose cytarabine, proton pump inhibitors, and colimycin without glycopeptides and the presence of chills were independent risk factors for gram-positive coccal infection. Mucositis was no longer associated with gram-positive coccal infection because of its strong relationship with use of proton pump inhibitors and colimycin use alone (P =.04 and P =.001, respectively). Trimethoprim-sulfamethoxazole (TMP-SMZ) use appeared to be a significant protective factor.

Table 2
Table 2

Comparisons of patients with and patients without gram-positive coccal infection.

On univariate analysis, use of high-dose cytarabine, use of colimycin without glycopeptides, and diarrhea at study enrollment were significantly associated with streptococcal infection, and use of colimycin without glycopeptides and inflammation of the catheter site were significantly associated with staphylococcal infection (table 3). On multivariate analysis, the independent risk factors for streptococcal infection were use of high-dose cytarabine, use of colimycin without glycopeptides, use of nonabsorbable antifungals, and diarrhea; for staphylococcal infection, only administration of colimycin without glycopeptides was found to be significant (table 4). There was a trend for TMP-SMZ use to protect from staphylococcal infection.

Table 3
Table 3

Comparisons of patients with streptococcal infection, patients with staphylococcal infection, and control subjects, on univariate analyses.

Table 4
Table 4

Comparisons of patients with streptococcal infection, patients with staphylococcal infection, and control subjects, on multivariate analysis.

GPRI. Each of the 4 independent risk factors for gram-positive coccal infection was assigned a value of 1 so that the GPRI ranged from 0 (no factor present) to 4 (all factors present). Table 5 shows the prevalence of and the relative risks for gram-positive and gram-negative infections, according to the GPRI. The risk for gram-positive infection increased 3.0, 3.9, 7.0, and 17.5 times when the GPRI was 1, 2, 3, and 4, respectively. For each additional point on the GPRI, the OR was 1.85 (95% CI, 1.43–2.38; P < 10-4) for gram-positive infection and 1.14 (95% CI, 0.81–1.61; P =.46) for gram-negative infection.

Table 5
Table 5

Prevalences and relative risks of gram-positive coccal and gram-negative infections, according to gram-positive risk index (GPRI).

The observed (20.5%) and expected (21.2%) numbers of gram-positive infections were similar; the high P value determined with use of the goodness-of-fit test indicated good agreement (calibration) (P >.50). The area under the ROC curve was 69% ± 16%.

SRI. Each of the 4 independent risk factors for streptococcal infection was assigned a value of 1. The prevalence of and relative risks for streptococcal, gram-negative, and staphylococcal infections according to the SRI are shown in table 6. The risk for streptococcal infection increased 2.9, 13.2, and 20.7 times when the SRI was 1, 2, and ⩾3 respectively. For each additional point on the SRI, the OR was 2.44 (95% CI, 1.69–3.52; P = 10-4) for streptococcal infection, 0.86 (95% CI, 0.63–1.19; P =.37) for gram-negative infection, and 1.27 (95% CI, 0.96–1.69; P =.09) for staphylococcal infection. The observed (7.8%) and expected (7.2%) numbers of streptococcal infections (P >.40) were similar. The area under the ROC curve was 76% ± 15%.

Table 6
Table 6

Prevalences and relative risks of streptococcal, gram-negative, and staphylococcal infections, according to streptococcal infection risk index (SRI).

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Discussion

This prospective epidemiologic study of 513 febrile neutropenic patients allowed us to establish predictive scores to optimize first-line treatment for febrile neutropenic patients with gram-positive coccal and streptococcal infections. The strengths of this study included prospective collection of data, unbiased patient recruitment and independent review, classification of patients according to outcome measures, and accurate measurement of risk factors. Our study population was representative of patients with febrile neutropenia hospitalized in French hematology centers, because 95% of the centers in France participated in the study. Furthermore, 96% of the consecutive patients were included in the analysis, which was largely because of the convenient 2-month study period and 1-month follow-up period.

In our study, the prevalence of gram-positive coccal infection (21%) was similar to that reported in prospective therapeutic trials [19–21], and the prevalence of streptococcal infection (7.8%) was in the lower range compared with other studies. Bacteremia due to viridans streptococci was detected in 4.7% of our patients and in up to 31% of patients described in other series [12]. Our overall mortality rate of 5% was consistent with that noted in antibiotic trials that involve patients with febrile neutropenia, and our mortality rate for patients infected with coagulase-negative staphylococci, which approached 0%, was similar to that reported in most other series [8, 19, 22, 23]. The mortality rate associated with α-hemolytic streptococcal bacteremia is 4%–18% [1, 2, 12, 13, 24–26], and, although low mortality rates have been reported [27], it is generally recognized that streptococcal bacteremia in neutropenic patients may progress rapidly to septic shock and acute respiratory distress syndrome, which require appropriate management to avoid irreversible septic complications [2, 5, 28, 29]. Previous retrospective studies of patients with bacteremia due to viridans streptococci have identified profound neutropenia, use of high-dose cytarabine therapy, mucositis, and use of histamine2 antagonists, antacids, quinolones, and TMP-SMZ as risk factors [1, 2, 3, 5, 8, 12, 13]. However, these findings have never been prospectively validated.

Our prospective study revealed that receipt of high-dose cytarabine, proton pump inhibitors, and colimycin without glycopeptides and presence of chills were independent risk factors for gram-positive coccal infections. Independent risk factors for streptococcal infections were use of high-dose cytarabine, colimycin without glycopeptides, and nonabsorbable antifungals and the occurrence of diarrhea. Although a retrospective study suggested that high-dose cytarabine therapy causes gut damage and favors the translocation of streptococci [13], no significant association between receipt of high-dose cytarabine and mucositis of any grade was observed in our series. On our multivariate analysis, oropharyngeal mucositis, which has previously been identified as a risk factor for streptococcal infection [2, 3, 27], was not associated with gram-positive coccal or streptococcal infection. This difference may have been due to the high incidence of mucositis (34%) in our control population. The low percentage of patients receiving quinolones in our series may have precluded us from showing the impact of these antibiotics on the occurrence of gram-positive coccal or streptococcal infection, as has been reported elsewhere [1, 2]. Although severe neutropenia has been significantly associated with infection due to viridans streptococci by means of comparison with control subjects who had other gram-positive infections [2], we observed only a trend on univariate analysis in our series. However, the high rate of severe neutropenia (69%) in our control population—including gram-negative bacteremia, which is usually associated with severe neutropenia [30]—compared with the 20% rate in the control population described by Elting et al. [2] may have precluded our ability to show any significant relationship between severe neutropenia and streptococcal infection. In our study, although the presence of chills at the time of study enrollment was significantly associated with gram-positive coccal infection (table 2), this was not the case when streptococcal infections and staphylococcal infections were analyzed separately. The most likely explanation for this difference is the lower power of our series of patients with streptococcal infection (table 3) compared with that in the study of Elting et al. [2].

Gram-positive coccal infections may have a gut origin. Such drugs as histamine2 antagonists, antacids, and sucralfate select patients with gut lesions and may favor streptococcal bacteremia [2] by increasing the gastric pH and so favor microbial growth and translocation from the gut. In our experience, the use of antiulcer drugs, especially proton pump inhibitors, was an independent risk factor for gram-positive coccal infection but was not significant for streptococcal infection, possibly because of the lower power of this series.

Gut decontamination with use of nonabsorbable antibiotics (mainly colimycin without glycopeptides) was a risk factor for both streptococcal and staphylococcal infections in our series. Because of the low number of enterococcal infections (n = 6), this effect is not explained by the effect of colimycin on enterococci overgrowth in the gut, as illustrated by animal models [31]. Although quinolone prophylaxis is seldom used in France, most patients receiving chemotherapy for acute leukemia and almost all allogeneic stem cell transplant recipients are given nonabsorbable antibiotics (usually colimycin and aminoglycosides) during the neutropenic phase. Consequently, approximately one-half of the patients in our study had received nonabsorbable antibiotics. Previous studies from countries in which gut decontamination is not performed could not identify this risk factor for gram-positive coccal infections [1–3].

Similarly, use of nonabsorbable antifungals, namely polyenes, was associated with an increased risk of streptococcal infection in our study. Several studies have reported bacteremia to be associated with antifungal prophylaxis, and a recent large study showed a relationship between use of both absorbable and nonabsorbable antifungals and bacteremia [30, 32–35]. Taken together, these findings argue in favor of the role of oral polyenes in gram-positive coccal growth. In contrast with a previous report, which showed that TMP-SMZ use increased the risk of streptococcal infection [2], we found that TMP-SMZ was associated with a decreased incidence of gram-positive coccal infection, but this was mainly the result of a decreased risk for staphylococcal infection.

Because β-lactams are widely used for empirical therapy for neutropenic patients, in line with international recommendations, the presence of gram-negative infection may have limited impact on the choice of initial treatment. More accurate identification of specific risk factors for streptococci could facilitate evaluation of the benefit of glycopeptides or other anti—gram-positive drugs in first-line treatment compared with results of previous trials [22, 23, 36]. As determined with our GPRI, the risk for gram-positive coccal infection increased 3-fold for patients with 1 risk factor at the onset of febrile neutropenia, and it increased 17.5-fold for patients with all 4 risk factors. Similarly, the relative risk for streptococcal infection increased from 2.9 to 20.7 according to the number of risk factors present. Because the GPRI was not relevant for gram-negative infection, and because the SRI was moderately relevant for staphylococcal infection, these 2 indexes should allow reasonably accurate prediction of the occurrence of gram-positive coccal infections in general and of streptococcal infections in particular. We are prospectively validating these 2 scores among a new cohort of neutropenic patients. Use of these indexes could improve the treatment of neutropenic patients and help investigators design antibacterial trials to specifically address the question of the best strategy to manage gram-positive coccal infections and streptococcal infections in this population.

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Investigators and Participating Centers

Investigators and participating centers (all of which are in France) are as follows: A. Auvrignon, Hôpital Trousseau, Paris; Bendahmane, Institut Gustave Roussy, Villejuif; C. Bergeron, Hôpital Sud, Rennes; C. Berthou, Centre Hospitalo-Universitaire (CHU) Augustin Morvan, Brest; M. Boasson, Centre Hospitalier Regional Universitaire (CHRU), Angers; O. Bouscary, Hôpital Cochin, Paris; P. Chastagner, Hôpital de Brabois, Vandoeuvre Les Nancy; L. Collet, Institut Paoli Calmettes, Marseille; P. Cony-Makhoul, Hôpital du Haut-Leveque, Pessac; J. Beaune, Hôpital Henri Mondor, Créteil; Th. De Revel, Hôpital du Val de Grâce, Paris; M. Delain, CHRU Bretonneau, Tours; M. Macro, CHU, Caen; B. Desablens, CHRU, Amiens; M. C. Escande, Institut Curie, Paris; N. Fegueux, CHR Lapeyronie, Montpellier; B. Girier, Hôpital Saint-Louis, Paris; H. Guy, Hôpital du Bocage, Dijon; D. Guyotat, Hôpital Nord, Saint-Etienne; Ph. Henon, Hôpital du Has, Mulhouse; R. Herbrecht and I. Zix-Kieffer, Hôpital de Hautepierre, Strasbourg; M. Hunault, Hôtel Dieu, Paris; H. Laurichesse, Hôpital de Clermont-Ferrand; O. Lortholary, Hôpital Avicennes, Bobigny; D. N'Daw, Hôpital Paul Brousse, Villejuif; G. Michel, Hôpital de La Timone, Marseille; N. Parquet, Hôpital Saint-Louis, Paris; A. M. Peny, Centre Francois Baclesse, Caen; Y. Perel, Hôpital Pellegrin, Bordeaux; C. Rose, Hôpital Huriez, Lille; L. Sutton, Pitié Salpétriere, Paris; M. Tiab, Hôpital de l'Hôtel Dieu, Nantes; A. Buzyn-Lévy, Hôpital Necker, Paris; P. Vic, Hôpital Huriez, Lille.

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Acknowledgements

We thank Jean-Pierre Ghanassia (Agence Medicom, Paris) and Martine Rozenbaum (Laboratoires Hoescht-Marion-Roussel, Paris), for help in design and management of the study, and Isabel Cunningham (Beth Israel Hospital, New York), for help in finalization of the manuscript.

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Footnotes

  • Financial support: The Club de Réflexion sur les Infections en Onco-Hématologie is part of the Institut Maurice Rapin (Paris). This study was supported by a grant from Laboratoires Roussel (Paris).

  • Received April 9, 2002.
  • Revision received September 30, 2002.
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  1. Clin Infect Dis. (2003) 36 (2): 149-158. doi: 10.1086/345435
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