Patients and methods

Patients' characteristics, antimicrobial regimen and transplantation procedure

In total, 38 patients undergoing matched related donor allogeneic transplantation at our institution were sequentially treated with meropenem (1 g q8h) starting on the day of the first febrile episode (n=17, group A) vs prophylactic meropenem (1 g q8h) starting on the first day with a granulocyte count <500/mm³ (n=21, group B), and maintained until resolution of fever or after granulocyte count >500/mm³ in both groups. All patients received cotrimoxazol (960 mg q12h p.o.) as prophylaxis against Pneumocystis carinii from day -9 to day -2 and then restarted once granulocyte counts reached >500/mm³ for 3 consecutive days until day +180 post transplant. In addition, HSV-positive patients received acyclovir 800 mg q12h p.o. at least up until day +30 and fluconazol (400 mg qd p.o.) or itraconazol (2.5 mg/kg q12h p.o.) at least up to day +75 after transplantation. In the event of fever lasting more than 72 h after the initial treatment, patients received vancomycin or teicoplanin in case of Gram-positive infection or amikacin or ciprofloxacyn in case of Gram-negative infection. Second-line antibiotherapy was also started according to clinical criteria (ie based on the site of infection). At 5–7 days after the first fever episode patients received antifungal treatment with conventional or lipo-somal amphotericin B.

Patients' characteristics are specified in Table 1. All patients received myeloablative-conditioning regimens based on busulphan and cyclophosphamide (n=22), cyclophosphamide and TBI (n=10) or other regimens (n=6). In all patients, GVHD prophylaxis consisted of cyclosporine A (CsA) 1.5 mg/kg q12h i.v. starting on day -7 and switched to an oral dose as soon as the patient could tolerate oral medication. In the absence of grade II or more acute GVHD, CsA was tapered 5% weekly starting day +50 and discontinued by day +180. CsA levels were monitored starting day +1 and were maintained in the therapeutic range (150–300 ng/ml) until tapering. MTX was given at a dose of 15 mg/m² i.v. on day +1 and 10 mg/m² i.v. on day +3, +6 and +11 followed by folinic acid rescue.

Table 1 - Patients and transplant characteristics.

Full table

Disease status at transplant was categorized as early in 22 cases (acute leukemia or poor-risk myelodysplasia in first complete remission, untreated low-risk myelodysplasia, first chronic-phase CML, lymphoid malignancy in first remission), intermediate in 10 patients (acute leukemia or myelodysplasia in second or higher complete remission, second chronic-phase CML, lymphoid malignancy in second or higher complete remission or partial response) and advanced in six cases (refractory or relapsed disease).

A Hickman catheter was inserted about 2 weeks before transplant and all patients were nursed in single rooms supplied with filtered air under positive pressure or laminar air flow. Hand washing by staff and care providers and conventional preventive strategies were performed with all patients.

No differences were observed between either subgroup of patients in terms of disease status, diagnosis, age, conditioning regimen or CMV serology. Hematopoietic stem cell source was bone marrow in three and four patients from groups A and B, respectively and peripheral blood in 14 and 17 patients from groups A and B, respectively; no differences were observed between either subgroup of patients.

Assessments

Patients were examined daily for symptoms and signs of infection. Body temperature was recorded at least four times daily and more often if clinically indicated. In the event of fever, blood cultures from a peripheral vein and from Hickman catheter were taken together with any other clinically relevant cultures. A febrile episode was defined as an oral temperature above 38°C for 2 h or more or a single temperature above 38.5°C. Response to antibiotherapy was defined as temperature <37.5°C at 72 h after commencement of therapy.

According to the EORTC criteria, infections were classified into four categories based on clinical findings, course of the febrile episode and microbiological data.

Microbiologically documented refers to a febrile episode accompanied by definite clinical signs and symptoms of infection plus microbiological confirmation from the original site (MDI: microbiologically documented infection). Bacteremia was defined as the occurrence of one positive blood culture specimen of Gram-negative organisms or Staphylococcus aureus or more than one positive culture for other Gram-positive bacteria. Clinically documented infection refers to a febrile episode accompanied by definite clinical signs and symptoms of infection but without specific microbiological proof. Unexplained fever refers to a febrile episode accompanied by equivocal signs and symptoms of infection without microbiological proof.

Statistical analysis

The influence of the different variables on fever, antibiotic requirements and infectious episodes was analyzed by nonparametric Mann–Whitney test and multiple linear regression. Other quantitative end points (number of antibiotics, antibiotic day, neutropenic days) were analyzed with the two-sample Wilcoxon test. Qualitative parameters were analyzed using ² test. The time to development of fever was evaluated using a Kaplan–Meier curve and the log-rank test. Significant factors were included in a multivariate analysis using a forward stepwise Cox proportional hazards regression model. Significance levels were set at 0.05.

Results

Post transplant outcome and noninfectious toxicity

Projected overall and event-free survival at 5 years were 57 and 51%. With a median follow-up of 548 days (47–2172 days), 15 (39%) patients have died, seven (18%) due to transplant-related mortality (TRM) and eight due to disease progression. Two out of the seven patients who died due to TRM developed bacterial (Acinetobacter lwoffi) and fungal infections that led to death. No significant differences were observed between patients receiving or not prophylaxis with meropenem in terms of early and overall TRM.

Regarding hematological toxicity, all evaluable patients except one reached >0.5 10⁹/l granulocytes at a median of 16 day (range: 10–32) and >20 10⁹/l platelets at a median of 12 days (range: 7–56 days). No significant differences in terms of hematological toxicity were observed between patients receiving (group B) and those not receiving (group A) prophylactic meropenem.

As far as grades 3–4 extra-hematological toxicity was concerned, 10% of patients developed liver toxicity, 63% mucositis, 10% nausea/vomiting, 3% neurologic toxicity, 10% diarrhea and 3% renal toxicity. Actuarial incidence of grades II–IV aGVHD was 50% and overall and extensive chronic GVHD was 70 and 55%, respectively. No significant differences in terms of extra-hematological toxicity were observed between the two subgroups of patients.

Infectious toxicity

Concerning infectious episodes, 16 (94%) out of 17 patients included in the group A developed fever in the early post transplant period as compared to 16 (76%) among patients in group B (log rank, P=0.02; Figure 1). The mean number of days of fever did not differ between the two subgroups (6 days in each arm). While only one patient did not require first-line therapy with broad spectrum antibiotics in group A, there were seven (33%) patients in group B who did not require modified antibiotherapy (P=0.01) since fever lasted less than 72 h and, more importantly, 11 (52%) patients in group B did not require a second line of antibiotics as compared to two (11%) of patients included in group A (P=0.04).

Figure 1.

Actuarial incidence of fever episodes.

Full figure and legend (25K)

As far as antibiotics were concerned, as previously specified, patients in group B received meropenem starting on the first day with a granulocyte count <500/mm³. Overall, median day to reach <500/mm³ granulocytes was day +2 after infusion (range: 0–4 days) while patients in group A received meropenem starting on the day of the first febrile episode, which occurred at a median of 7 days after transplant (range: 0–20). Nevertheless, due to the lower incidence of both febrile episodes and the need for second-line therapy, patients in group A received a mean of 18 days (s.d.=10 days) of antibiotics as compared to 15 days (s.d.=13 days) among those patients included in group B (P=0.43). In addition, the use of empirical antifungal therapy did not differ between the two subgroups (35 and 33% received the therapy in groups A and B, respectively). Finally, the mean days of hospital stay were 35 and 32 days for groups A and B, respectively (P=0.4).

Disease status at transplant also significantly influenced the development of febrile episodes (73% of patients in early stage developed fever as compared to 100% among patients with intermediate or advanced disease status, P<0.001). Other variables such as progenitor cell source, sex, CMV serology, GVHD or conditioning regimen did not significantly influence the development of febrile episodes (Table 2). The median days of neutropenia were 16 days among patients whether or not they developed any febrile episode. All variables with a 'P'-value <0.1 were included in a multivariate analysis and both antibiotic prophylaxis (HR for those not receiving prophylaxis=2.83, 95% CI (1–8.02); P=0.04) and disease status at transplant (HR for patients in early stage=0.15, 95% CI (0.04–0.62); P=0.04) significantly influenced the development of febrile episodes.

Table 2 - Analysis of variables with any impact on febrile episodes.

Full table

Infections were microbiologically documented in 12 patients (six cases from each group). In nine patients, Gram-positive bacteremias were documented and in five of them methicillin-resistant staphylococci were isolated. All five of these cases corresponded to the nonprophylaxis arm while in the remaining four patients (two from each group) non-methicillin-resistant staphylococci were isolated. In three cases, Gram-negative microorganisms were isolated: Escherichia coli documented in a urine culture in a patient included in group A and A. lwoffi documented in blood culture in two patients included in group B. Interestingly, in one of these patients, bacteremia occurred after engraftment and meropenem had already been discontinued, while in the second patient included in group B bacteremia occurred before stem cell infusion. Interestingly, the microorganism was sensitive to meropenem in both cases.

Concerning the two patients who died specifically due to infectious toxicity, one of them, included in group B, had developed a bacteremia (A. lwoffi) while off meropenem and the other patient, included in group A, died due to a fungal infection.

Discussion

Information regarding the use of antibiotic prophylaxis in the early post transplant period among patients receiving allogeneic transplantation is scanty and controversial. In fact, most data refer to small subsets of transplanted patients included within large series of cancer patients undergoing conventional chemotherapy. In previous studies, patients receiving quinolone prophylaxis had a 35% reduction in MDIs and 46% decrease in total infections as compared to those who did not receive prophylaxis.^{12,13,14,15,16} In the few trials performed in bone marrow recipients,^24,25,26,27 oral quinolones effectively prevented Gram-negative infections and delayed febrile episodes, thus suggesting a positive impact on outcome through antibiotic prophylaxis.

Nevertheless, several problems have emerged from the use of quinolone prophylaxis. First of all, an elevated risk for Gram-positive infections has been noted in several trials.¹⁹ Furthermore, a major concern is that quinolone prophylaxis may increase the risk for developing infections with resistant bacteria as reported in several studies carried out in patients treated with conventional chemotherapy,^{17,18,20,21,22,23} which showed that patients receiving fluoro-quinolone prophylaxis rapidly become colonized with quinolone-resistant E. coli and coagulase-negative staphylococci. In this sense, two oncology units who gave quinolone prophylaxis have documented the nosocomial spread of fluoroquinolone-resistant coagulase-negative staphylococci.^19,28,29 The addition of penicillin or roxithromicin to the fluorquinolone can reduce the risk of streptococcal infection.^30,31 However, resistance to penicillin is emerging.³² Moreover, three trials have failed to demonstrate any difference in febrile episodes using quinolone prophylaxis.^15,33

Carbapenems have a wide spectrum of activity including Gram-positive bacteria such as Streptococci viridans, Gram-negative bacteria including Pseudomonas aeruginosa and anaerobic bacteria. This wide spectrum of activity and their low range of toxicity supports the use of these antibiotics in the allogeneic transplant setting. Meropenem used as monotherapy in neutropenic patients has shown a similar efficacy as compared to combined therapy. In the present study, we have evaluated the efficacy of antibiotic prophylaxis with meropenem started on the first day with a granulocyte count <500/mm³ after matched related donor stem cell transplantation, and we have observed that with this approach a significant proportion of patients do not develop fever during the early post trasplant period. While previous studies performed in bone marrow recipients^24,25,26,27 have only shown a delay in febrile episodes by using quinolone prophylaxis, the present study shows both a significant delay and reduction of febrile episodes.

An important issue regarding the prophylactic use of antibiotics in the allogeneic transplant setting is the emergence of widespread antibiotic resistance, and different guidelines have been proposed to minimize this risk.³⁴ Interestingly, in our study, no meropenem-resistant bacte-ria has been isolated, suggesting that to start prophylaxis only when granulocyte counts are <500/mm³, that is, during the period of higher risk of infection, minimizes the number of days of exposure to the drug and reduces the risk of developing infections with resistant bacteria, as reported in several studies using other approaches.^{18,19,20,21,22,23} Nevertheless, this approach should be monitored carefully and, in the absence of fever, meropenem should be discontinued when >500 granulocytes/mm³ are reached in order to minimize the days of exposure to the antibiotic and to avoid multiresistant bacteria. In addition, we have not observed an increased risk for Gram-positive infections among patients receiving prophylaxis with meropenem, nor an increased risk of fungal infections as suggested by both culture analysis and the similar number of days of antifungal therapy required for patients whether or not they received prophylaxis.

The economic impact of the procedure is another important aspect regarding the use of prophylaxis with any antibiotics. In the current study, we have confirmed that, although patients receiving prophylaxis started meropenem when granulocyte counts were <500/mm³ (median of 2 days after transplant) and patients who did not receive it started antibiotics at a median of 7 days after transplant, those who were finally included in the prophylaxis group received antibiotics during a mean of 15 days as compared to 18 days among those included in the nonprophylaxis arm. This is mainly due to the lower incidence of febrile episodes among patients in group B and also to the higher percentage of patients in group A who required a second line of antibiotics.

In conclusion, this pilot study suggests that the use of prophylaxis with meropenem during the period of neutropenia in patients undergoing allogeneic stem cell transplantation favorably affects the morbidity of the procedure by reducing the febrile episodes without significantly increasing the risk of infection from multiresistant bacteria although further studies using PCR to evidence genetic mutations and larger number of patients would be required to confirm these results. In addition, this approach does not increase the overall costs of the procedure since it does not increase the total number of days of antibiotherapy.

References

1. Feroze Momin MD, Pranatharthi H, Chandrasekar MD. Antimicrobial prophylaxis in bone marrow transplantation. Ann Intern Med 1995; 123: 205–215. | PubMed |
2. van der Meer JW, Guiot HF, van der Broek PJ, van Furth R. Infections in bone marrow transplant recipients. Semin Hematol 1984; 21: 123–140. | PubMed | ChemPort |
3. Beelen DW, Haralambie E, Brandt H et al. Evidence that sustained growth supresion of intestinal anaerobic bacteria reduces the risk of acute graft versus host disease after sibling marrow transplantation. Blood 1992; 80: 2668–2676. | PubMed | ISI |
4. Pizzo PA. Considerations for the prevention of the infectious complications in immunosuppressed patients with cancer. Rev Infect Dis 1989; 11: 1551–1563.
5. Metcalf D. The colony stimulating factors: discovery, development, and clinical applications. Cancer 1990; 65: 1286–1295. | PubMed |
6. Nemunaitis J, Rabinowe SN, Singer JW et al. Recombinant granulocyte–macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med 1991; 324: 1773–1778. | PubMed | ISI | ChemPort |
7. Advani R, Chao NJ, Horning SJ et al. Granulocyte–macrophage colony-stimulating factor (GM-CSF) as an adjunct to autologous hematopoietic stem cell transplantation for lymphoma. Ann Intern Med 1992; 116: 183–189. | PubMed | ISI | ChemPort |
8. Powles R, Smith C, Milan S et al. Human recombinant GM-CSF in allogeneic bone marrow transplantation for leukemia: double-blind, placebo-controlled trial. Lancet 1990; 336: 1417–1420. | Article | PubMed | ISI | ChemPort |
9. Eric AE, Joseph L, Michael B. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998; 16: 1179–1187. | PubMed | ChemPort |
10. Lew MA, Kehoe K, Ritz J et al. Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation. Transplantation 1991; 51: 630–636. | PubMed | ISI |
11. Maiche AG, Muhonen T. Granulocyte colony-stimulating factor (G-CSF) with or without a quinolone in the prevention of infection in cancer patients. Eur J Cancer 1993; 29: 1403–1405. | Article |
12. Karp JE, Merz WG, Hendricksen C et al. Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1987; 106: 1–7. | PubMed | ISI | ChemPort |
13. Bow EJ, Rayner E, Louie TJ. Comparison of norfloxacin with cotrimoxazole for infection prophylaxis in acute leukemia. The trade-off for reduced gram-negative sepsis. Am J Med 1988; 84: 847–854. | Article | PubMed | ISI |
14. Cruciani M, Concia E, Navarra A et al. Prophylactic cotrimoxazole versus norfloxacin in neutropenic children – perspective ramdomized study. Infection 1989; 17: 65–69. | Article | PubMed | ISI |
15. Lew MA, Kehoe K, Ritz J et al. Ciprofloxacin versus trimethopim/sulfamethoxazole for prophylaxis of bacterial infections in bone marrow transplant recipients: a randomized, controlled trial. J Clin Oncol 1995; 13: 239–250. | PubMed | ISI | ChemPort |
16. Yeh SP, Hsueh EJ, Yu MS, Wang YC. Oral ciprofloxacin as antibacterial prophylaxis after allogeneic bone marrow transplantation: a reappraisal. Bone Marrow Transplant 1999; 24: 1207–1211. | Article | PubMed | ISI | ChemPort |
17. Cometta A, Calandra T, Bille J, Glauser MP. Escherichia coli resistant to fluoroquinolones in patients with cancer and neutropenia. N Engl J Med 1994; 330: 1240–1241. | Article | PubMed | ISI |
18. Carratalá J, Fernández-Sevilla A, Tubau F et al. Emergence of quinolone resistant Escherichia coli bacteriemia in neutropenic patients with cancer who have received prophylactic norfloxacin. Clin Infect Dis 1995; 20: 557–560. | PubMed | ChemPort |
19. Kotilainen P, Nikoskelainen J, Huovinen P. Emergence if ciprofloxacin-resistant coagulase-negative staphylococcal skin flora in immunocompromised patients receiving ciprofloxacin. J Infect Dis 1990; 16: 41–44.
20. Kern WV, Markus A, Andriof E. Bacteriemia due to fluoro-quinolone-resistant Escherichia coli in two immunocompromised patients. Eur J Clin Microbiol Infect Dis 1994; 13: 161–165. | Article | PubMed | ISI |
21. Kern WV, Andriof E, Oethinger M et al. Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center. Antimicrob Agents Chemother 1994; 38: 681–687. | PubMed | ISI | ChemPort |
22. Alarcón T, Pita J, López-Brea M, Piddock LJ. High-level quinolone resistance amongst clinical isolates of Escherichia coli and Klebsiella pneumoniae from Spain. J Antimicrob Chemother 1993; 32: 605–609. | PubMed |
23. Ena J, López-Perezagua MM, Martinez-Peinado C et al. Emergence of ciprofloxacin resístanse in Escherichia coli isolates after widespread use of fluoroquinolones. Diagn Microbiol Infect Dis 1998; 30: 103–107. | Article | PubMed | ISI |
24. Schmeisser T, Kurrle E, Arnold R et al. Norfloxacin for the prevention of bacterial infection during severe granulocyto-penia after bone marrow transplantation. Scand J Infect Dis 1988; 20: 625–631. | PubMed |
25. Menichetti F, Felicini R, Bucaneve G et al. Norfloxacin prophylaxis for neutropenic patients undergoing bone marrow transplantation. Bone Marrow Transplant 1989; 4: 489–492. | PubMed | ISI |
26. Lew MA, Kehoe K, Ritz J et al. Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation. Transplantation 1991; 51: 630–636. | PubMed | ISI |
27. Krochinsky F, Wichmann G, Bornhauser M et al. Efficacy and tolerability of prophylaxic treatment with intravenous piperacillin/tazobactam in patients undergoing hematopoietic stem cell transplantation. Transplant Infect Dis 2002; 4: 132–136.
28. Classen DC, Burke JP, Ford CD et al. Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis. Am J Med 1990; 89: 441–446. | Article | PubMed | ISI |
29. Oppenheim BA, Hartley JW, Lee W, Burnie JP. Outbreak of coagulase negative staphylococcus highly resistant to ciprofloxacin in a leukemia unit. BMJ 1989; 299: 294–297. | PubMed |
30. Broun ER, Wheat JL, Kneebone PH et al. Randomized trial of the addition of gram-positive prophylaxis to standard antimicrobial prophylaxis for patients undergoing autologous bone marrow transplantation. Antimicrob Agents Chemother 1994; 38: 576–579. | PubMed | ISI |
31. Kern WV, Hay B, Kern P et al. A randomized trial of reoxithromycin in patients with acute leukemia and bone marrow transplant recipients receiving fluoroquinolone prophylaxis. Antimicrob Agents Chemother 1994; 38: 465–472. | PubMed | ISI |
32. Guiot HFL, Corel LJA, Bossen JMHJ. Prevalence of penicillin-resistant viridians streptococci in healthy children and in patients with malignant haematological disorders. Eur J Clin Microbiol Infect Dis 1994; 13: 645–650. | Article | PubMed | ISI |
33. Orlandi E, Navarra A, Cruciani M et al. Norfloxacin versus cotrimoxazole for infection prophylaxis in granulocytopenic patients with acute leukemia. A prospective randomized study. Haematologica 1990; 75: 296–298. | PubMed | ISI |
34. Shales DM, Gerding DN, John JF et al. Society for healthcare epidemiology of America and infectious diseases society of America joint committee on the prevention of antimicrobial resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997; 25: 584–599. | PubMed | ISI | ChemPort |