Bone Marrow Transplantation (2002) 29, 367–371 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Mini-review Antibiotic prophylaxis in patients receiving hematopoietic stem cell transplant KA Sepkowitz Clinical Infectious Diseases Section, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Summary: Oral prophylaxis: background and rationale Effective prophylaxis against specific infections has allowed increasingly potent conditioning regimens to be For decades, various approaches have been tried in an given, thereby prolonging survival in HSCT recipients. attempt to reduce the risk of translocated oral and bowel The Centers for Disease Control and Prevention, in col- flora, which, along with central venous catheters, are the laboration with numerous professional societies, has source of the overwhelming majority of episodes of serious recently published guidelines to codify and advance this bacterial infection in the cancer and HSCT patient. The approach. Controversy remains in several areas but, goal is an important one and the intervention seems simple: curiously, the most intense debate concerns prevention just knock out the bowel and mouth flora with antibiotics. of bacterial infections, the most extensively studied of To this end, numerous regimens through the years have all of the approaches. Central to this debate are the been tried, included neomycin and polymyxin, trimethoprim– competing priorities of a potentially ill patient on the sulfamethoxazole and, most recently, the oral quinolones, one hand vs the long-term consequences of unchecked particularly ciprofloxacin.2–4 antibiotic use. The emergence in the 1990s of vancomy- Despite the logic of reducing bowel and mouth flora with cin-resistant Enterococcus demonstrated all too vividly antibiotics, thereby reducing the risk of subsequent bactere- how devastating such an end result could be. This arti- mia, there is no consensus that this is the right thing to do.5– cle will review the arguments for and against the routine 8 Preliminary work has even suggested that ciprofloxacin use of antibacterial prophylaxis in HSCT recipients. without metronidazole given as prophylaxis might promote Bone Marrow Transplantation (2002) 29, 367–371. DOI: development of graft-versus-host disease9 and that cipro- 10.1038/sj/bmt/1703366 floxacin alone may be associated with an increased risk of Keywords: bacterial infections; prophylaxis; drug resist- leukemia relapse among HSCT recipients.10 ance; sepsis In general, the infectious disease community, citing the concern of promoting drug resistance, has been hesitant about making this a routine approach, while the oncology community, with a specific patient in front of them whom Clinicians have long sought a means of preventing infec- they are trying to keep out of the hospital, has been more tions among those receiving hematopoietic stem cell trans- enthusiastic. plantation (HSCT). Although advances have been made in What then is the evidence for routine use of oral antibac- preventing certain infections such as Pneumocystis carinii terial prophylaxis? A well-conducted meta-analysis of trials 1 and Candida albicans, prevention of bacterial infections using ciprofloxacin as the agent of choice for prophylaxis arising from routine enteric flora, which contribute a sub- of patients with neutropenia was published in 1996.2 The stantial amount of infectious morbidity, has been more dif- authors compared trials of various quinolones vs another ficult. prophylactic treatment (trimethoprim–sulfamethoxazole, This review will consider both sides of the ongoing argu- non-absorbable agents, or placebo). In all, results from ment on optimal management: the noble goal of briefer and 2112 patients were included, representing 19 studies. fewer hospitalizations with less mortality vs the inevitable The authors found that, as hoped, the rate of Gram-nega- consequence of antibiotic use: drug resistance. tive bacteremias was reduced. Furthermore, unlike many other reports, there was no evidence for an increase in Gram-positive bacteremias. Both of these findings are exciting and important. Furthermore, in general, most clin- icians believe their patients benefit from therapy. That was the good news. The more problematic finding Correspondence: KA Sepkowitz, Infectious Diseases Service, Memorial was that neither days with fever nor patient mortality was Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY reduced. In other words, the intervention successfully low- 10021, USA ers risk for certain types of bacteremia, some of them Antibiotic prophylaxis in HSCT recipients KA Sepkowitz 368 extremely serious, but, in the final analysis, has very little tuberculosis strains resistant to streptomycin. A similar positive impact on the patient’s overall health or survival. phenomenon occurred when penicillin was introduced into A more recent meta-analysis examining a comparable hospitals in the 1950s: Staphylococcus aureus quickly group of studies reached a similar and perhaps even more developed resistance and rendered the drug useless in this cautious conclusion.3 In this report, which included 1408 therapeutic context. And so within moments after the wide- subjects from 18 studies (some included in the first meta- spread introduction into practice of that great twentieth cen- analysis), the authors found a reduction in infection-related tury miracle – antibiotics – the bitter irony of drug resist- outcomes but no difference in mortality. Furthermore, the ance was born. difference in fever-days was modest overall and non-exi- The two basic tenets governing this unfortunate circum- stent in blinded studies. stance are simple and unalterably true: (1) the bacteria, Not only that, the authors voiced a concern about the sooner or later, will always prevail, given their vast num- long-term consequences of such an approach: not necessar- bers; (2) the more antibiotic given, the faster resistance ily to the actual patient at hand, but to future patients. emerges. Specifically they raised the specter of drug resistance The fate of Escherichia coli susceptibility is quite telling resulting from unchecked antibiotic use. As they concluded, in this regard11 (Table 2). E. coli is the most common the emergence of resistant bacteria ‘threatens to undermine Gram-negative bacterium causing bacteremia among neu- the long-term efficacy of prophylaxis with fluoroquino- tropenic hosts in most series. Researchers from the EORTC lones’. followed the fate of E. coli as quinolone use was introduced Resistant bacteria are only one of several real concerns into common practice in Europe. They identified two arising from the practice of routinely prescribing oral important consequences. First, the prevalence of resistant agents to prevent bacterial infections. Also important to E. coli rose quickly during the 11-year study period (from consider are other unintended consequences of this none to 28% resistance), which was hardly a surprise. approach, each of them with potentially deleterious effects Second, and more unexpectedly, the rate and resistance pat- not just to the current group of patients being treated with tern to the quinolones of coagulase-negative Staphylo- HSCT, but those who will require this treatment in the com- coccus increased sharply as well, from none to 61% resist- ing years (Table 1). Although the practice of oral prophy- ance. This demonstrated that, in addition to the desired (and laxis is all but routine in many HSCT centers, the current undesired) effect of an intervention, any change in approach problems with drug resistance may force a careful recon- may exert an unintended influence, in this case on an ‘inno- sideration of this still unproved approach. cent bystander’ pathogen that has emerged as the most Clinical situations with clear risk from a predictable and common cause of catheter-related bacteremia. This is dis- easily prevented organism, such as Streptococcus pneumon- cussed in more detail below under ‘unexpected pathogens’. iae in patients with chronic GVHD, lie outside the debate.1 In this example, the consequences of no intervention far outweigh those arising from chronic penicillin therapy and Vancomycin-resistant Enterococcus prophylaxis must be given.1 The E. coli data alarmed some but not all practitioners. For many, the threat of emergent drug resistance, similar to the Emergence of drug resistance threat of military bioterrorism, was considered the result of the overheated imagination of the infectious Gram-negative organisms disease/infection control community. Yet this dark fear became everyone’s collective nightmare in the 1990s with Within months of the first doses of streptomycin, given for the rapid appearance internationally of vancomycin-resist- tuberculous meningitis in the 1940s, came reports of ant Enterococcus (VRE).12 Few hospital-based infections Table 1 Arguments for and against use of routine prophylaxis to prevent bacterial infections among HSCT recipients Arguments in favor Arguments against Gut decontamination Fewer Gram-negative bacteremias No change in mortality rates Possibly less fever Possibly more Gram-positive infections Possibly briefer hospitalization Loss of quinolones as subsequent therapeutic option Promotion of antibiotic resistance Promotion of non-susceptible organisms (eg, S. viridans) Monotherapy Less toxicity Possibly blunts emergence of resistance Less nurse/pharmacy time committed Possibly more efficient bacterial killing Broader initial empiric spectrum Out-patient