Prophylactic Antimicrobial Agents and the Importance of Fitness
【关键词】 Antimicrobial,
Improved management of infectious complications of cancer has contributed substantially to the success of care over the past several decades. In the 1960s it became clear that neutropenia was highly correlated with the occurrence of rapidly progressive sepsis.1 In the 1970s, strategies for empirical antibacterial therapy were devised to minimize these complications. This therapy was directed primarily against gram-negative rods, especially Pseudomonas aeruginosa, with good results.2 Paradoxically, this strategy has caused gram-positive cocci to become the most frequent cause of bacteremia among patients with cancer. However, the need for empirical treatment of infections with gram-positive cocci is rare because they are associated with a lower rate of acute morbidity. In the 1980s, empirical therapy was devised against invasive fungal infections, and the 1990s saw the development of oral empirical antibacterial therapy administered on an outpatient basis in low-risk patients.3,4 All these strategies are predicated on an understanding of the clinical phenotype at risk, the pathogen or pathogens of concern, and the period of greatest risk.
Many investigators have attempted to extend the benefits of early therapy by administering antimicrobial agents in a prophylactic rather than empirical fashion, such as from the initiation of chemotherapy to engraftment; however, the results of these studies with respect to effectiveness have been mixed and have aroused concern about side effects, both expected and unexpected,5 and the emergence of resistant organisms.6,7 Guidelines do not advocate the use of such an approach.8,9 A prophylactic strategy should diminish the attack rate and delay the time to the onset of an infectious complication, but rarely does it obviate the risk of infection (Figure 1). The goal is to provide a modicum of protection during a vulnerable period, such as during neutropenia and mucositis. This issue of the Journal includes two well-performed, large, randomized, double-blind, placebo-controlled trials of prophylactic fluoroquinolone therapy in patients undergoing cancer chemotherapy ― one by Bucaneve et al.10 and one by Cullen and colleagues.11 The data from these two studies far exceed the combined data from the numerous previously available studies.7
Figure 1. Effect of Antimicrobial Prophylaxis on the Rate of and Time to Infection.
Antimicrobial prophylaxis typically diminishes and delays the occurrence of an infection but rarely obviates the risk.
Central to a successful prophylactic strategy is an understanding of the clinical phenotype at risk. At first blush, the populations in the two studies appear similar: they both consisted of patients undergoing chemotherapy for solid tumors or lymphoma who were at risk for prolonged, severe neutropenia. Bucaneve and colleagues studied patients at higher risk, including inpatients undergoing therapy for leukemia or an autologous hematopoietic stem-cell transplantation. Cullen et al. studied outpatients who were receiving multiple cycles of chemotherapy but not cytokine growth factors or an autologous hematopoietic stem-cell transplant. The prophylactic intervention was thus deployed differently in these two studies, given the differences in perceived risk. Bucaneve et al. administered levofloxacin from about the time of the initiation of chemotherapy until engraftment, and Cullen et al. used levofloxacin therapy for the seven days estimated to coincide with the nadir of the white-cell count during each cycle of chemotherapy (maximum, six cycles). Both groups used a similar primary end point: the occurrence of a fever. As expected, infection was definitively documented in a minority of episodes of febrile neutropenia, since there are many causes of fever in this patient population. The differences between patients enrolled in these two studies are reflected by a 10-fold difference in the rate of febrile episodes in the placebo groups: 85 percent in the study by Bucaneve et al., as compared with 7.9 percent (during the first chemotherapy cycle) in the study by Cullen et al. The challenge of using fever as a primary end point is great, since it occurred despite antimicrobial prophylaxis in 65 percent and 3.5 percent of the patients, respectively.
Cullen and colleagues report multiple, substantial benefits of their prophylactic strategy, including a significant decrease in the relative risk of a first febrile episode by 56 percent, of any febrile episode by 29 percent, of probable infection during the first cycle by 28 percent, and of hospitalization during any cycle by 36 percent. However, the absolute reductions in the risk of these events were 4.4 percent, 4.4 percent, 5.4 percent, and 3.6 percent, respectively. The use of levofloxacin prophylaxis protected 35 patients against the primary end point of fever. To achieve this benefit, approximately 20,000 doses of levofloxacin were administered. Alternatively, if these data are analyzed according to the number of cycles of chemotherapy, the absolute risk of a febrile episode is 4.3 percent per cycle in the placebo group and 2.9 percent per cycle in the levofloxacin group. The number of patients treated per cycle to avoid one febrile episode is approximately 70. Prophylactic levofloxacin had no protective effect against the risk of severe infection or death and was associated with an absolute increase in the incidence of side effects (occurring in 78 patients, as compared with 40 patients in the placebo group) of 1.1 percentage point.
Bucaneve et al. also reported a significant reduction in the rate of febrile episodes, positive cultures, bacteremias, and infections with gram-negative rods with the use of levofloxacin prophylaxis but no survival benefit. The rate of febrile episodes was unusually high: 85 percent in the placebo group and 65 percent in the levofloxacin group. The number of patients who needed to be treated to avoid a single episode of febrile neutropenia was estimated to be five. The levofloxacin group had a lower rate of Escherichia coli bacteremia than did the placebo group (1.2 percent [4 of 336 patients] vs. 3.0 percent [10 of 337 patients]), but this was associated with an increased rate of levofloxacin resistance (77 percent [10 of 13 isolates] vs. 17 percent [4 of 24 isolates]). The findings regarding resistance were similar for gram-positive organisms (respective rates of 91 percent [31 of 34 isolates] and 64 percent [28 of 44 isolates]). Thus, the use of levofloxacin prophylaxis led to a decrease in the overall rate of documented bacterial infection but a substantial increase in the rate of documented infections with resistant organisms.
All antibiotic interventions come at a price, including increased costs, side effects, susceptibility to enteric infections, and emergence of resistant endogenous organisms.6,12 Many patients are reluctant to increase the number of pills they must take, as evidenced by the 20 percent of patients in the study by Bucaneve et al. who declined to take any of the study medication. How should a patient who is receiving a fluoroquinolone prophylactically be treated when febrile neutropenia develops? The use of established empirical outpatient regimens of oral agents is probably unwise because they include a fluoroquinolone.3,4 By decreasing colonization resistance, increased use of antimicrobial agents increases patients' susceptibility to nosocomial infections (e.g., with Clostridium difficile) as well as community-acquired infections (e.g., salmonellosis)13 that cause diarrhea. This susceptibility may be increased for months after exposure to the antimicrobial agent.12 It is difficult to measure accurately the many potential consequences of a broadly applied strategy of antimicrobial prophylaxis.
The most important issue to weigh is the potential for emergence, amplification, and dissemination of antimicrobial-resistant organisms. Several factors must be considered, including the reservoir for the organisms, the selective pressure on this reservoir, the resistance threshold of a given organism to a given antimicrobial agent, and the fitness cost of the resistance determinant (i.e., the effect on the replication capacity of the organism). What effect does the degree of use of antimicrobial agents proposed by these studies have on the patient's flora and the collective flora of those in the cancer center? What is the time dependency of this evolutionary process?
The prophylactic use of fluoroquinolones has already been associated with the synchronous emergence of resistant gram-negative rods in patients undergoing cancer chemotherapy, thus implying that the resistance threshold is not high.14 There is little diminution of fitness in fluoroquinolone-resistant gram-negative rods15 such as E. coli, and once a resistant clone becomes established, it is difficult to control. Since the emergence and dissemination of antimicrobial resistance take time, it is very difficult to assess all the implications in an exhaustive manner. As resistant organisms emerge at a given center, the use of broad-spectrum antimicrobial agents will increase, further accelerating this evolutionary process. One way to maintain the benefits described in the two current studies but minimize the risk is to restrict its use to those at highest risk. For example, in the report by Cullen et al., nearly half the benefit in terms of the reduction of febrile neutropenic events appears to have occurred in patients who had fever during a previous cycle. Too few data are presented to analyze this difference fully, but it is important to attempt to identify those at highest risk to optimize the balance of risks and benefits.
The studies by Bucaneve et al. and Cullen et al. provide important data on a key question in the treatment of patients undergoing cancer chemotherapy. However, the following factors still need to be defined: the patients at greatest risk, the period of increased risk, and the likelihood of the emergence of resistant organisms. Efforts to improve risk stratification will be critical to minimize unnecessary use of antimicrobial agents and simultaneously preserve the benefits described in the two studies. Because resistant organisms will emerge, the application of this strategy of prophylaxis requires dynamic monitoring. If prophylactic antimicrobial therapy is to be adopted at a cancer center, it should be accompanied by vigorous infection-control practices and careful monitoring for the emergence of resistant organisms. Bucaneve et al. and Cullen et al. provide evidence of the significant benefit of levofloxacin prophylaxis, but the price of this benefit may be high.
References
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