Little to Be Gained by Quinolone Prophylaxis in Cancer Neutropenia

TORONTO—Neutropenic cancer patients are often given quinolones in an attempt to ward off infection, but a recent metaanalysis suggests that little is gained from prophylaxis. Furthermore, development of quinolone resistance in such patients may deprive clinicians of an effective oral therapy that could be used as outpatient treatment in patients who do develop infections.

Speaking at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Eric A. Engels, MD, and his colleagues presented data showing that quinolones reduce the occurrence of gram-negative infections but have little effect on infection-related mortality or on the occurrence of fevers.

“Quinolone prophylaxis is commonly used for neutropenic cancer patients, but the evidence in support of the use of quinolones to reduce infection during that neutropenic period is mixed,” Dr. Engels said in an interview.

He noted that it is difficult to arrive at a consensus because the numerous studies give uncertain, and at times conflicting, conclusions about the true benefit of quinolone prophylaxis. “We set out to do a systematic and quantitative meta-analysis of the randomized trials looking at prophylaxis in that population,” Dr. Engels said.

The researchers included all randomized controlled trials in which quinolone prophylaxis was compared either with no prophylaxis or with trimethoprim-sulfamethoxazole (TMS) in patients who became neutropenic during cancer chemotherapy. Those trials included patients with acute leukemia, lymphomas and solid tumors, and those undergoing bone marrow transplantation.

Eighteen such trials were identified. Trials were selected after an extensive literature search and were not limited to trials reported in English.

The investigators separately analyzed randomized clinical trials comparing quinolones with no prophylaxis (9 trials, 731 subjects) and randomized clinical trials comparing quinolones with TMS (9 trials, 677 subjects). The quinolones studied included ciprofloxacin (Cipro), ofloxacin (Floxin), enoxacin (Penetrex), and norfloxacin (Noroxin).

From each trial arm, the investigators extracted the proportion of subjects with each outcome of interest (fever, infection, or death) and pooled relative risk estimates using a random effects model. They also pooled estimates of incidence of quinolone-resistant infections.

Reduces Gram-Negative Risk

The analysis showed that quinolone prophylaxis did not significantly reduce the risk of fevers or infection-related mortality, although it did reduce the risk of gram-negative, microbiologically documented, and total infections (Table). Among the quinolone recipients, 3% developed infections with quinolone-resistant gram-negative rods, and 8% developed infections with quinolone-resistant gram-positive cocci.

“Quinolones clearly reduce the occurrence of documented gram-negative infections. That is not surprising given their spectrum of activity,” Dr. Engels said. The culture-proven infections included many gram-negative infections, gram-positive infections, and fungal infections. Dr. Engels said that the significant reduction in total culture-proven infections was mostly due to the substantial reduction in gram-negative infections.

Quinolones also were clearly more effective than TMS at preventing gram-negative infections, but there was no significant effect on risk of gram-positive infections.

“The risk of fevers was unchanged, so we suspect that quinolone prophylaxis does not prevent the need for hospital admissions and intravenous antibiotics, although we did not look at hospitalization or empiric antibiotic use per se,” Dr. Engels said.

As to the lack of a reduction in mortality, he pointed out that even though gram-negative infections have an attributable mortality in this population, it may be that management of these infections is effective enough that no significant benefit is gained from prophylaxis.

This study raises major questions about the current widespread use of quinolones in nonfebrile neutropenic cancer patients. “If quinolone prophylaxis does not reduce mortality, the need for hospitalization, or the need for empiric antibiotic use, its benefit is questionable,” Dr. Engels said.

The study found no harm from prophylactic use of quinolones, but also no great benefit. This raises the question of what to recommend. “Basically,” he said, “we reached the same conclusion as the Infectious Disease Society of America, that prophylaxis is not of significant benefit to patients with neutropenia and should probably not be used.”

The biggest concern, he noted, is antibiotic resistance and the risk that widespread use of the quinolones may destroy their usefulness. “We saw a lot of evidence at the ICAAC meeting that quinolone-resistant bacteria are becoming increasing problems in our hospitals, our communities, and our cancer centers,” he said. “Current data suggest that the emergence of resistance is inevitable, so we need to use our antibiotics wisely.”

This point assumes greater importance given the evidence that oral quinolones may be effective outpatient therapy for febrile neutropenic cancer patients, he noted. “Quinolone therapy is not an available option in a patient who has already developed quinolone-resistant organisms due to perhaps unnecessary prophylactic use,” he said.

Dr. Engels concluded that more research and certainly more discussion about the appropriateness of quinolone prophylaxis in neutropenic cancer patients are urgently needed. “The incidence of quinolone-resistant infections appears low, but surveillance is needed, since resistant infections may appear only after widespread use of quinolones,” he said.