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Antibiotic prophylaxis during neutropenia

Antibiotic prophylaxis during neutropenia. New evidence Implications for practice. Anat Gafter-Gvili, Abigail Fraser, Mical Paul Leonard Leibovici Rabin Medical Center, Beilinson Campus. 2002 IDSA guidelines.

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Antibiotic prophylaxis during neutropenia

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  1. Antibiotic prophylaxis during neutropenia New evidence Implications for practice Anat Gafter-Gvili, Abigail Fraser, Mical Paul Leonard Leibovici Rabin Medical Center, Beilinson Campus

  2. 2002 IDSA guidelines “Data supporting the efficacy of prophylaxis … in reducing the number of infectious episodes during the neutropenic period are adequate … However, concern about the problem of emerging drug-resistant bacteria and fungi due to extensive antibiotic use, plus the fact that such prophylaxis has not been shown to consistently reduce mortality rates, leads to the recommendation that routine prophylaxis with these drugs in neutropenic patients be avoided…” Hughes et al. Clin Infect Dis 34, 2002

  3. New evidence • Two large contemporary RCTs 1, 2 • Re-evaluation of the combined evidence accumulated in RCTs through systematic review and meta-analysis 3 • Bucaneve et al. N Engl J med Sep 8, 2005 • Cullen et al. N Engl J med Sep 8, 2005 • Gafter-Gvili et al. Ann Intern Med Jun 21, 2005

  4. GIMEMA trial • RCT, double blind placebo-controlled • 760 adults with acute leukemia, solid tumors or lymphoma (90% BMT) with neutropenia expected to last >7 days • Multicenter, Italy 2001-2003 • Levofloxacin vs. placebo administered at the time of chemotherapy or re-infusion of stem cells until neutropenia resolution • Primary outcome: occurrence of fever requiring empiricalantibacterial therapy during neutropenia • Secondary outcome: All-cause mortality Bucaneve et al. N Engl J med Sep 8, 2005

  5. SIGNIFICANT trial • RCT, double blind placebo-controlled • 1565 adults with solid tumors or lymphoma • Multicenter, UK 1999-2003 • Levofloxacin vs. placebo for 7 days during the anticipatedperiod of neutropenia of each chemotherapy cycle, for up to six cyclesof chemotherapy • Primary outcome: any fever attributed to infection, throughout all cycles and during the first cycle • Mortality was not an outcome Cullen et al. N Engl J med Sep 8, 2005

  6. Cochrane review • Systematic review with meta-analysis • Inclusion of all RCTs • Any antibiotic/s vs. placebo or other antibiotic/s • All types of patients • Primary outcome: all cause mortality • Power to demonstrate a difference in mortality • Accounting for beneficial and adverse effects • Inclusion of cancer-related mortality Protocol first published: The Cochrane Library July, 2003 Journal publication: Ann Intern Med Jun 21, 2005 Full Cochrane review: The Cochrane Library Oct, 2005

  7. Objectives • To update our previous systematic review and meta-analysis with the two new large RCTs • To test whether antibiotic prophylaxis reduces mortality in different types of neutropenic patients (high risk vs. low risk) • To formulate implications for clinical practice, based on the new data

  8. Methods • We searched The Cochrane Library, EMBASE and MEDLINE with no date restrictions • References of all included studies were scanned for additional studies • Authors were contacted for information regarding unpublished trials or complementary data on their own trial

  9. Inclusion Criteria • We included randomized controlled trials comparing antibiotic therapy with placebo, no intervention, or with other antibiotics, for prophylaxis of bacterial infections in neutropenic patients • Trials were included irrespective of publication status and language

  10. Data extraction • Two reviewers independently applied inclusion criteria and extracted the data, and assessed the quality of included trials • Each of the following components were individually assessed: allocation concealment, generation of the allocation sequence, blinding, and exclusions after randomization

  11. Data analysis • Relative risks with 95% confidence intervals were calculated for individual trials • Results were pooled using the fixed effect model. When significant heterogeneity was detected we used the random effects model

  12. Included trials • One-hundred and one studies performed between the years 1973 to 2005 were included • The trials randomized 12599 patients, mostly adults • Fifty-six trials compared a prophylactic antibiotic to placebo or no intervention, • of which 22 evaluated fluoroquinolones

  13. Results

  14. Quinolone vs. control 16 studies, 3545 patients RR 0.55 (95% CI 0.40-0.70) All-cause mortality Any antibiotic vs. control 42 studies, 5211patients RR 0.66 (95% CI 0.55-0.79)

  15. Quinolone vs. control 12 studies, 3323 participants RR 0.49 (95% CI 0.31-0.77) Infection-related mortality Any antibiotic vs. control 39 studies, 5238 participants RR 0.59 (95% CI 0.47-0.75)

  16. Quinolone vs. control 21 studies, 3699 participants RR 0.73 (95% CI 0.64-0.84) Febrile patients Any antibiotic vs. control 49 studies, 6023 participants RR 0.78 (95% CI 0.71-0.86) Random effects model

  17. Quinolone vs. control 17 studies, 3409 participants RR 0.61 (95% CI 0.46-0.81) Clinically documented infections Any antibiotic vs. control 44 studies, 5278 participants RR 0.67 (95% CI 0.58-0.78) Random effects model

  18. Quinolone vs. control 20 studies, 3647 participants RR 0.49 (95% CI 0.36-0.66) Microbiologically- documented infections Any antibiotic vs. control 49 studies, 5948 participants RR 0.52 (95% CI 0.44-0.63) Random effects model

  19. Quinolone vs. control 18 studies, 3647 participants RR 0.58 (95% CI 0.50-0.68) Any bacteremia Any antibiotic vs. control 49 studies, 5947 participants RR 0.52 (95% CI 0.47-0.59)

  20. Quinolone vs. control 18 studies, 2949 participants RR 0.35 (95% CI 0.25-0.49) Gram-negative bacteremia Any antibiotic vs. control 37 studies, 4920 participants RR 0.44 (95% CI 0.35-0.54)

  21. Gram-positive bacteremia Quinolones RR 0.77 (95% CI 0.63-0.96) Cotrimoxazole RR 0.38 (95% CI 0.24-0.60) Other systemic RR 0.58 (95% CI 0.38-0.89) Overall RR 0.65 (95% CI 0.55-0.78) Levofloxacin RR 0.58 (95% CI 0.42-0.79)

  22. Thus far… • New evidence shows a reduction in all-cause mortality with antibiotic prophylaxis • Mediated most probably by a reduction in infectious complications

  23. The questions • Which drugs and schedule should we use? • Which patients should be offered prophylaxis? • What is the balance between the gains from prophylaxis vs. its costs and drawbacks? • Are there major determinants of prophylaxis efficacy that are sufficiently different in our practice from the randomized controlled trials, to justify withholding antibiotic prophylaxis?

  24. The questions • Which drugs and schedule should we use? • Which patients should be offered prophylaxis? • What is the balance between the gains from prophylaxis vs. its costs and drawbacks? • Are there major determinants of prophylaxis efficacy that are sufficiently different in our practice from the randomized controlled trials, to justify withholding antibiotic prophylaxis?

  25. Quinolones vs. TMP-SMZ • TMP-SMZ was used initially, but this agent has several disadvantages including side-effects and prolongation of neutropenia • Fluoroquinolones were introduced in the 1980’s and became popular due to their broad antimicrobial spectrum, preservation of anaerobic gut flora, systemic bactericidal activity and lack of myelosuppression

  26. Quinolones vs. cotrimoxazole PCP?

  27. Quinolone vs. control 1980-2005 RR 0.55 (95% CI 0.40-0.70) All-cause mortality Cotrimoxazole vs. control 1978-1987 RR 0.71 (95% CI 0.49-1.02)

  28. Choice of quinolone

  29. Schedule With chemotherapy 32 trials RR 0.66 (95% CI 0.53-0.83) With neutropenia 9 trials RR 0.66 (95% CI 0.48-0.90)

  30. Antibiotic selection and schedule • Ciprofloxacin or levofloxacin • Local pathogen distribution and susceptibilities • Convenience • Administered with chemotherapy/ stem cell transplantation in AL/ BMT • Administered at the time of anticipated neutropenia for solid cancer

  31. The questions • Which drugs and schedule should we use? • Which patients should be offered prophylaxis? • What is the balance between the gains from prophylaxis vs. its costs and drawbacks? • Are there major determinants of prophylaxis efficacy that are sufficiently different in our practice from the randomized controlled trials, to justify withholding antibiotic prophylaxis?

  32. Quinolones vs. placebo

  33. Quinolones for acute leukemia/ BMT NNT to prevent 1 death = 1/ RD = 1/ (0.055 – 0.58*0.055) = 43 patients

  34. Costs and detriments • Drug costs • Adverse events • Fungal infections • Resistance development

  35. Toxicity and Tolerability • Fluoroquinolones are used widely both in hospital practice and in the community and are known to be well tolerated with an acceptable safety profile

  36. Quinolone vs. control 14 studies, 1071 participants RR 0.83 (95% CI 0.56-1.22) Documented fungal infections Any antibiotic vs. control 38 studies, 2682 participants RR 1.07 (95% CI 0.83-1.37)

  37. Resistance development • The individual: colonization followed by infection with resistant microorganisms in the neutropenic individual, thus affecting health and chance of survival • Micro-environment: change in the flora of the ward or unit in which this practice is adopted, thus potentially harming other patients • Macro-environment: change in resistance to fluoroquinolones in the population at large.

  38. Existing data

  39. The individual • No difference in quinolone-resistant infections • Total antibiotic consumption probably decreased with prophylaxis • When infection develops, quinolone resistance in 30% • No data regarding resistance to other antibiotics • As the overall mortality is reduced by prophylaxis, the danger of infection caused by resistant pathogens to a particular patient is evidently much smaller than the gain.

  40. The micro-environmentObservational Studies • Several observational studies examined the outcomes of neutropenic patients in settings with high resistance to quinolones when the practice of prophylaxis is discontinued: • Kern et al. Eur J Clin Microbiol Infect Dis; 2005; 24: 111-118 – Germany: ofloxacin prophylaxis stopped in 1998: GNB bacteremia rose from 8% (13 of 160 patients) to 20% (20 of 100). • Reuter et al. CID 2005; 40: 1087-1093– Germany: after a 12 month period of levofloxacin prophylaxis (2003), a period of discontinuation was stopped prematurely after 9 neutropenic episodes after 3 weeks due to a high mortality rate: 33.3% (3 of 9) versus 2.9% (9 of 310). • Delarive et al. Schweiz Med Wochenschr 2000; 130: 1837-44– Switzerland: Discontinuation of ciprofloxacin prophylaxis (1994) led to an increase in febrile episodes and Gram-negative bacteremia, without an increase in total bacteremia. There was a non-significant increase in mortality: No deaths among 41 patients which received ciprofloxacin, compared with 3 deaths among 71 patients given no prophylaxis. • Martino et al. Acta Haematol 1998;99:206-211 – Spain: discontinuation of norfloxacin (1995) led to a non-significant increase in febrile episodes and bacteremia. • Gomez et al. Cancer 2003:97:419-24 – Spain: discontinuation of ciprofloxacin (1996) did not affect incidence of febrile neutropenia and bacteremia.

  41. The micro-environment • No quantitative data • The ethics of withholding a clearly effective antibiotic drug from present patients to reserve it for future patients are far from clear.

  42. The macro-environment • The quantity of fluoroquinolones to be given as prophylaxis to neutropenic patients is negligible compared to the consumption of fluoroquinolones for other infections, e.g. of the urinary tract Acute leukemia: 0.012% All cancers: 0.47% UTI women – 13% UTI men 2% Yearly incidence

  43. Altogether – AL/ BMT • Patients with acute leukemia/ BMT should be offered antibiotic prophylaxis • Basing on a reduction in all-cause mortality with a low number of patients needed to treat • No evidence for adverse resistance-induction impact on the individual • No grounds for withholding treatment basing on other ecological considerations

  44. Quinolones for patients with solid tumors/ lymphoma NNT to prevent 1 death = 1/ RD = 1/ (0.025 – 0.51*0.025) = 82 patients

  45. The SIGNIFICANT trial • Significant reduction • Febrile episodes: 56% for the first cycle and 29% for all cycles • Clinically documented infections: 28% for 1st cycle and 18% overall • Hospitalizations: 36% for 1st cycle and 27% overall • Non significant reduction in mortality • NNT 132 patients for the 1st chemotherapy cycle Cullen et al. N Engl J med Sep 8, 2005

  46. Altogether – solid cancer/ LY • Advantage probable for the first chemotherapy cycle • More data needed on specific patient sub-groups • Quinolone prophylaxis precludes the use of oral empirical therapy for low-risk patients with febrile neutropenia

  47. The questions • Which drugs and schedule should we use? • Which patients should be offered prophylaxis? • What is the balance between the gains from prophylaxis vs. its costs and drawbacks? • Are there major determinants of prophylaxis efficacy that are sufficiently different in our practice from the randomized controlled trials, to justify withholding antibiotic prophylaxis?

  48. Prevalence of quinolone resistance • GIMEMA trial • Control group quinolone resistance (bacteremia) • Overall: 47% • Gram-negative bacteria: 17% • Prevalence of quinolone resistance in Italy • Gram-negative bacteria: 20% Bucaneve et al. N Engl J med Sep 8, 2005

  49. Prevalence of Gram-positive infections • Fluoroquinolones are active mainly against Gram-negative bacteria • Gram-negative infections are lethal • Gram-positive : Gram-negative bacteria ratio in existing trials • GIMEMA trial: 1.3 (61:47) • Other trials after 2000 : 1.0 • Even in the settings with relatively high prevalence of Gram-positive pathogens, prophylaxis is effective

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