The broad-spectrum antibiotic tigecycline, when added to the standard of piperacillin or tazobactam, appears to improve the empiric treatment of febrile neutropenia in patients with leukemia and other hematologic malignancies.
In a study in the May 10 issue of the Journal of Clinical Oncology (2014;32:1463-1471), a team led by Giampaolo Bucaneve, MD, of Hospital Policlinico Monteluce in Perugia, Italy, reported that favorable outcomes were 23 percent better for patients treated with the addition of tigecycline than with monotherapy with piperacillin/tazobactam.
Antibiotic monotherapy is currently the front-line empiric treatment for such patients, but increasingly resistant organisms have led to attempts to use antibiotic combinations to treat infections, he explained.
Tigecycline is the first of a new class of broad-spectrum antibiotics known as glycylcyclines—third-generation tetracyclines developed specifically to address antibiotic resistance—to be approved in the United States. After granting priority new drug review, the U.S. Food and Drug Administration approved tigecycline in 2005 for treating complicated intra-abdominal and skin-structure infections, and in 2009 for community-acquired bacterial pneumonia.
The new trial was an open-label study comparing the resolution of febrile episodes, without modifications of the initial allocated treatment, in 390 patients who received intravenous piperacillin/tazobactam at 4.5 g every eight hours, with or without 50 mg of tigecycline every 12 hours, after a loading dose of 100 mg.
A total of 187 of the patients received IV piperacillin/tazobactam plus tigecycline and 203 received IV monotherapy with piperacillin or tazobactam. The majority of the patients had leukemia, although approximately one quarter had lymphoma or other blood malignancies.
Almost 70 percent of patients in the tigecycline group responded to treatment and had successful outcomes, compared with only 44.3 percent of monotherapy patients, for an absolute difference in risk of 23.6 percent. The rates were significantly better in patients with microbiologically and clinically documented infections—61.4 versus 28.1 percent. The rates for clinically documented infections were 84.2 versus 47.4 percent in the monotherapy group.
Mortality rates were 8.5 percent in the combination group and 7.4 percent with standard monotherapy. Deaths attributed to infection were 5.8 versus 5.4 percent in the two groups, while bacteremia deaths were 4.2 percent in the tigecycline group versus 3.9 percent. Adverse events occurred in 6.4 percent of patients in both groups.
First Such Study
“To our knowledge, this is the first multicenter, randomized, controlled, prospective trial powered to demonstrate that the combination of piperacillin/tazobactam with tigecycline is more effective than piperacillin/tazobactam alone for the empiric treatment of fever in persistently granulocytopenic patients with cancer,” Bucaneve said in an interview, adding that the combination was safe and well tolerated.
Immediate empirical antibiotic therapy is necessary for all patients with acute leukemia who present with fever and neutropenia, he said, and patients should receive antibiotics to treat both gram-positive and gram-negative pathogens.
“In settings with a high prevalence of infections because of multidrug-resistant microorganisms, this combination could be considered as one of the first-line empiric antibiotic therapies, and should be started within 48 hours of signs of infection.”
The researchers reported that tigecycline combined with an antipseudomonal agent was effective regardless of the site of the infection, but a significantly better response to the combined regimen was observed against bacteremias, especially those due to Staphylococci and Escherichia coli (E coli).
Because a majority of the subjects were leukemia patients who had received intensive chemotherapy, the researchers said the findings may not be as applicable in patients with other types of cancer, those undergoing less intensive chemotherapy, and those not receiving quinolones prophylaxis.
In 2012 the Expert Group of the 4th European Conference on Infections in Leukemia issued guidelines for initial empirical therapy in febrile neutropenic patients, based on the local resistance epidemiology and patient risk factors for resistant bacteria and for a complicated clinical course. In patients without risk factors, the panel recommended an “escalation” approach, avoiding empirical carbapenems and combinations, while a “de-escalation” approach with initial broad-spectrum antibiotics or combinations—including tigecycline—be used only in those with the above risks, and that treatment be started within 48 hours.
However, the consensus conference also noted that evidence “is scanty at best” that combinations, such as those including tigecycline, improve outcomes or prevent the emergence of resistance.
Limit to Certain Centers
Asked for her opinion, Alison Freifeld, MD, Professor in the Division of Infectious Disease at the University of Nebraska Medical Center, who helped develop the Infectious Diseases Society of America's clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer, said the results of the JCO study are not surprising given the expanded spectrum of coverage afforded by tigecycline added to piperacillin and tazobactam.
“This is a well-done multicenter trial,” she said, “but I feel its importance and application should currently be limited to centers in which there is a high level of gram-negative resistance among E. coli or Klebsiella blood stream infections (BSI) that might be most impacted by the tigecycline addition—but not for those with pseudomonas or other gram-negative BSIs, and where fluoroquinolone resistance is of greatest importance among enterobacteriaceae.”
She said the combination also appears to be an effective therapy for patients with coagulase-negative staphylococci (coNS) and staph auras bacteremias, but it is not clear that these organisms require upfront therapy for all patients in order to treat the few who actually have the disease: “Thus [the treatment] is useful for clinically documented infections but has no significant effect on fever of unknown origin, pneumonias, abdominal, or central venous catheter infections.”
She also noted that the study found no overall effect on mortality, or death due to infections. “Differences in efficacy were based entirely on the need for a modification of the allocated antibiotic regimen, which is perhaps an overly strict endpoint since many patients will require some kind of modification if there is a narrower coverage upfront versus a broader regimen such as the combination,” she said.
Friefeld added that other cautions are that the trial was open-label and used a limited study population—i.e., only autologous transplant patients with hematologic malignancies were studied. Nonetheless, she said, extrapolating the results could be considered to those with such malignancies where the duration of neutropenia is expected to be longer than seven to 10 days.