1. 1 Antibiotic prophylaxis for patients with acute leukemia Leukemia & Lymphoma, February 2008; 49(2): 183 – 193

2. Introduction Patients with hematologic malignancies, including acute leukemia (AL) Endogenous flora of the patient’s gastrointestinal tract Risk for bacterial infection –Treatment-related neutropenia –Gastrointestinal mucosal injury In the past, infection was the most common cause of death among patients with AL accounting for up to 75% of mortality. Antibiotics prophylaxis –Incidence of fever ↓ –Microbiologically documented infection ↓ –Lack of mortality benefit Few of these trials about the impact of prophylaxis on rates of infection and colonization with antibiotic-resistant bacteria or the clinical impact of infection with resistant bacteria Current evidence for antibiotic prophylaxis in patients with AL –Benefits –Risks such as emergence of clinically significant antibiotic resistant bacterial colonization and infection

3. Rational use of prophylaxis Decision about use of antibiotic prophylaxis –Individual’s susceptibility to infection –Potential adverse consequences Only patients who are most susceptible to infection will derive proper benefit from prophylaxis.

4. Considerations for prophylaxis

5. Prevalence and clincal impact of the event The event that is trying to be prevented must be well defined, serious enough, and prevalent enough to merit prevention –Primarily bacterial infection –Secondarily subsequent infection-related morbidity and death Kinetics of gram-negative bacteremia –Rapid morbidity and death, particularly if there is a delay in therapy Fever, neither a sensitive nor a specific marker for infection –36% of the patients without clear clinical or microbiological evidence of infection by Bucaneve et al. –Unexplained fever during a neutropenic as high as 40% Fever during neutropenia triggers the empiric use of antibiotics. –Utilization and toxicities of empiric antibiotics in comparison to prophylactic antibiotics –Cost benefit of prophylaxis

6. Susceptibility of the host to the event Physical factors –Mucositis –Central venous catheters Hematologic factors –Type of AL : AML vs ALL –Depth and duration of neutropenia Microbiologic factors –MRSA –drug-resistant Salmonella species in the community

7. Adverse consequences associated with prophylaxis Immediate adverse events –Allergic reaction –Non-infectious antibiotic-associated diarrhea –Drug fever Time-delayed adverse events –Alterations in the colonizing flora

8. Benefits of prophylaxis (I) Majority of bacterial infections in neutropenic patients with AL by gram-negative organisms including P. aeruginosa and E. coli Selective decontamination –Less pathogenic anaerobic organisms were unaffected by the ‘decolonizing’ antibiotic and would continue to colonize the gastrointestinal tract thereby preventing re-colonization by pathogenic Enterobacteriaceae. First absorbable oral antibiotic, trimethoprim-sulfamethoxazole for selective decontamination and prevention of infection in patients with AL during neutropenia –Significant reduction in proven bacterial infections by Enno et al. in 1978 –Fewer microbiologically documented infections by Gualtieri et al. –No differene by Weiser et al.

9. Benefits of prophylaxis (II) The first quinolone for use in prophylaxis, norfloxacin –Poorly oral bioavailability → high concentration in the GI tract –Karp et al. in an early trial 68 patients undergoing chemotherapy for AL Significantly fewer gram-negative infections No difference in the number of gram-positive infections, overall infections or death Newer quinolones, levofloxacin, a 3rd generation quinolone, and moxifloxacin, a 4th generation quinolone –Broad gram negative activity –Excellent oral absorption –Better gram-positive activity

10. Benefits of prophylaxis (III) Bucaneve et al. –Multicenter trial of 760 patients undergoing chemotherapy expected to cause neutropenia for greater than 7 days –Levofloxacin –Hematologic malignancies, ½ chemotherapy for AL –Fever, microbiologically documented infection ↓ –No difference in terms of clinically documented infection and death –Levofloxacin resistant gram negative bacteremia  → ‘Prophylaxis is associated with few overall bacteremias but increased infection with antibiotic-resistant organisms.’ Impact of quinolone prophylaxis on mortality –Debating issue : prophylasis failure, salvage antibiotics –Metaanalysis by Leibovici – significant lower risk of death On subanalysis of patients undergoing treatment for AL or stem cell transplantation –Significant reduction in the risk of death –Subanalysis span 18 years –Five different quinolones

11. Consequences of prophylaxis Based on the evidence described above, many cancer centers have adopted antibiotic prophylaxis for patients with AL. In the last twenty years, increases in colonization and infection with resistant and unusual pathogens Predominate organisms : from G(-) to G(+) pathogens –Widespread use of quinolone antibiotics –Use of new chemotherapeutic regimens causing more severe mucositis –Increased use of central venous catheters Viridans streptococci and coagulase-negative staphylococci are now the most commonly reported bloodstream isolates from febrile patients with neutropenia at some centers. Quinolone-resistant E. coli

12. Viridans streptococci (I) In the early 1990s, Elting et al., ‘alpha strep shock syndrome’ Typically viridans streptococci are insensitive to quinolone. Kern’s study –286 strains of viridans streptococci –Ofloxacin prophylaxis for AL –Nearly all of the isolates were cross-resistant to ofloxacin, norfloxacin and ciprofloxacin. → Selection for quinolone-resistant viridans streptococcal colonization of the oropharynx of cancer patients →  risk for infection with quinolone-resistant viridans streptococci On multivariate analysisby Elting et al. –Antibiotic prophylaxis with either quinolones or trimethoprim-sulfamethoxazole as a significant risk factor for viridans streptococcal bacteremia Timmers et al. about levofloxacin –Progressive resistance –Levofloxacin associated with resistant viridans streptococcal bacteremia

13. Viridans streptococci (II) Razonable et al. –Six episodes of viridans streptococcal bacteremia among 37 patients on levofloxacin prophylaxis undergoing stem cell transplant –All isolates had reduced susceptibility to levofloxacin and most also showed cross-resistance to moxifloxacin. Tunkel and Sepkowitz –44% of the viridans streptococci isolated at Memorial Sloan-Kettering Cancer Center during 2000 were resistant to penicillin. Carratala et al. –57% of the viridans streptococci isolated in their center over a six-year period were penicillin resistant. –Administration of a beta-lactam antibiotic within the previous two weeks Bochud et al. –Quinolone prophylaxis versus quinolone plus penicillin prophylaxis –Overall decrease in the rates of viridans streptococci bacteremia –All of the episodes of viridans streptococcal bacteremia in the penicillin group were penicillin-resistant.

14. Staphylococcal species Coagulase-negative staphylococci and Staphylococcus aureus –Widespread use of central venous catheter Coagulase-negative staphylococcal bacteremia associated with increasing use of quinolone prophylaxis MRSA –Moran et al. found that the majority of infections were due to S. aureus, 78% of which were due to MRSA. –Antibiotic exposure in the previous month

15. Clostridium difficile C. difficile-associated diarrhea is a well-known potential consequence of antibiotic therapy in hospitalized and chronically ill patients. On multivariate analysis, eposure to any quinolone within the preceding 6 weeks A recent observational study performed by von Baum et al. suggests that moxifloxacin may be associated with an even higher risk for C. difficileassociated diarrhea than other quinolones.

16. Salmonella Glynn et al. reported that antibiotic exposure within 4 weeks was significantly associated with increased susceptibility to infection. Patients who received antibiotics within 4 weeks were specifically at higher risk for acquiring multidrug- resistant infection. Other reports have described increased susceptibility to drug- resistant Salmonella enterica and Salmonella typhimurium in patients exposed to antibiotics up to 6 months before.

17. Quinolone-resistant Escherichia coli (I) The rise in quinolone-resistant E. coli at cancer centers has paralleled the increasing use of quinolones for prophylaxis in neutropenic patients. Heavy quinolone use at a cancer center, as generated by quinolone prophylaxis, may lead to a very high overall prevalence of quinolone-resistant E. coli infections. Initiation of quinolone prophylaxis at a center with a high background rate of quinolone-resistant E. coli infection (>15 – 20%) may have little or no preventative effect on bacteremia or fever. In addition, the initiation of prophylaxis at a center with a high background rate of quinolone-resistant E. coli infection comes at the cost of increased sustained rates of quinolone-resistant E. coli infection.

18. Quinolone-resistant Escherichia coli (II) Greater mortality in quinolone-resistant gram-negative infection –Quinolone-resistant stains of E. coli were significantly more likely to be resistant to other antimicrobial agents including ampicillin, trimethoprim-sulfamethoxazole, and gentamicin. –Delay in appropriate antimicrobial therapy is common and may be the underlying reason for higher mortality. Infection caused by quinolone-resistant E. coli in patients with AL is typically preceded by gastrointestinal colonization. Oethinger et al. reported that colonization persisted while the patients remained on quinolone prophylaxis for up to three months. Persistence of colonization by resistant E. coli suggests that risk for resistant infection may persist during subsequent cycles of chemotherapy, particularly if quinolone prophylaxis is used repeatedly. Prophylaxis can lead to increased complexity in the treatment of low risk fever and neutropenia.

19. Conclusions Significant risk of infection and subsequent infection-related morbidity and death during chemotherapy-induced neutropenia in patients with AL Prophylactic quinolone –Short-term benefits including reduced incidence of fever and gram-negative bacterial infection No placebo-controlled randomized trial has shown a reduction in death with the use of prophylactic antibiotics in this population. Furthermore, none of the published trials have assessed the long-term impact of prophylaxis on colonization and infection with antibiotic-resistant or unusual organisms nor can they assess the changing dynamics of the predominant circulating flora. Only those patients with AL who are most susceptible to infection during the highest risk period should be considered for prophylaxis.