Infectious Complications
Engels EA, Lau J, Barza M
J Clin Oncol 16(3):1179-1187, 1998

This meta-analysis was conducted to estimate the efficacy of quinolone antibiotics in preventing infections, fevers, and deaths among cancer patients who become neutropenic following chemotherapy. The authors searched MEDLINE for randomized trials of quinolone prophylaxis, controlled either with no prophylaxis or trimethoprim/sulfamethoxazole (TMS) prophylaxis. Relative risks for outcomes were pooled using a random-effects model. Eighteen trials with 1408 subjects were included. Compared with no prophylaxis, quinolones significantly reduced the incidence of gram-negative bacterial infections (relative risk [RR], 0.21), microbiologically documented infections (RR, 0.65), total infections (RR, 0.54), and fevers (RR, 0.85). Quinolone prophylaxis did not alter the incidence of gram-positive bacterial, fungal, or clinically documented infections, or of infection-related deaths. Results were similar for trials that used TMS as the control regimen. Among those who received quinolones, the incidence of infections due to quinolone-resistant organisms was 3.0% (95% CI, 1.7%-5.2%) for gram-negative species and 9.4% (95% CI, 5.3%-16.3%) for gram-positive species. Based on limited data, the incidence of quinolone-resistant infections was not higher among quinolone recipients than controls. With fever as outcome, blinded trials found quinolones less efficacious than did unblinded trials. The authors concluded that quinolone prophylaxis substantially reduces the incidence of various infection-related outcomes, but not deaths, in these patients. Although this reduction in infections may translate into a decrease in morbidity, the reduction in fevers (and by extension, use of empiric antibiotics) appears small, and blinded trials provided less evidence for benefit than unblinded trials. While quinolone-resistant infections are uncommon, they said, continued vigilance is warranted.

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Meropol NJ, Wood DE, Nemunaitis J, et al
J Clin Oncol 16(3):1167-1173, 1998

This prospective, randomized, placebo-controlled study was conducted to determine whether G-M CSF, when administered perioperatively, could reduce the incidence of surgical infections in cancer patients. Cancer patients at high risk of infectious surgical morbidity were randomized to receive G-M CSF 125mcg/m/day or placebo subcutaneously for 8 days beginning 3 days preoperatively. Routine antibiotic prophylaxis was administered to all patients. Of 399 patients enrolled, 198 were randomized to receive G-M CSF. During the first 2 weeks postoperatively, 21% of patients had infections, and there was no difference in infection rate between the study groups. The most common sites of infection were respiratory tract (53%) and surgical wound (25%). Duration of operation and American Society of Anesthesiology physical status classification were the most significant predictors of infection in multivariate analysis. G-M CSF was well tolerated and was not associated with fever. The authors concluded that the eligibility criteria for this study successfully defined a patient subgroup at high risk for postoperative infections. At an immunomodulatory dose of 125mcg/m/day, G-M CSF was safe and well tolerated by this subgroup, but it did not reduce the incidence of postoperative infections.

Can the Rate of Infections Be Reduced?
Editorial Comment by Gerald P. Bodey, MD Gynecologic Cancer

Infection remains a serious complication for patients undergoing cancer therapy. Tremendous progress has been made in the treatment of these infections, yet they continue to cause substantial morbidity and may lead to delays in the administration of cancer chemotherapy or necessitate reductions in the dosages of chemotherapeutic agents. Interest in the prevention of infection in neutropenic patients began in the 1960s. Initially, efforts were directed toward providing maximum protection with filtered air, barrier isolation, specially prepared food, and nonabsorbable antimicrobial regimens. This interest intensified when broad-spectrum orally absorbable antimicrobials became available, beginning with trimethoprim/sulfamethoxazole (TMS) and subsequently, the quinolones. Despite the widespread use of quinolone prophylaxis in neutropenic patients, there is considerable controversy regarding the use of these agents.

Engels and colleagues have addressed this controversy in their meta-analysis of the published randomized controlled studies of quinolone prophylaxis in neutropenic patients. They included 18 trials in which various quinolones were compared with no prophylaxis or TMS prophylaxis. In some studies, both patient groups received antifungal prophylaxis. They concluded from their analysis that quinolone prophylaxis significantly reduces the frequency of febrile episodes, total infections, and microbiologically documented infections, due to the reduced frequency of gram-negative bacterial infections. Quinolone prophylaxis did not reduce the frequency of gram-positive bacterial infections, clinically documented infections, or infection-related deaths, nor did they find a higher frequency of quinolone-resistant infections among the recipients of prophylaxis.

Unfortunately, this meta-analysis does not shed much new light on the value of quinolone prophylaxis, nor does it resolve the controversies. As is generally true with meta-analyses, these were disparate studies comprising different patient populations who received different chemotherapies and even different prophylactic regimens. Consequently, the duration of neutropenia and other patient risks varied considerably. Although 1408 patients were included in the analysis, 7 of the 18 studies included fewer than 60 total patients (age range, 18-59 years). In most studies, patients were not routinely assessed for colonization by quinolone-resistant bacteria. It is not surprising that quinolone resistance was not found to be a problem, since it often requires extensive use of an antibiotic before resistance becomes problematic. There have been several reports of small epidemics of quinolone-resistant gram-negative bacteremias on oncology wards where prophylaxis has been used. Also, although this analysis failed to demonstrate it, quinolone prophylaxis has been one of the factors associated with the increase in gram-positive infections in neutropenic patients. The authors confirm that quinolones are effective for preventing gram-negative bacterial infections, and they rightly raise cautions regarding their usage. Certainly, quinolone prophylaxis can be justified for some neutropenic patients, but it should be reserved for only those patients at greatest risk of infection.

A totally different approach to infection prophylaxis is addressed by Meropol and associates -- the use of granulocyte-macrophage colony-stimulating factor (G-M CSF) for patients undergoing oncologic surgery. This multi-institutional prospective randomized study included 399 patients, half of whom received G-M CSF for 3 days prior to and 5 days after surgery. Patients undergoing a wide variety of surgical procedures were included, although 41% of patients had abdominal surgeries. There was no difference in the frequencies of infectious complications between the 2 groups during the first 2 postoperative weeks (21% vs 22%). Respiratory and wound infections were most common. The most important risk factor for infection was the duration of surgery, and G-M CSF provided no decrease in infections among the group of patients undergoing prolonged procedures. G-M CSF did cause an increase in the number of circulating neutrophils, and toxicities were infrequent. Laboratory studies have demonstrated that G-M CSF enhances neutrophil and macrophage/monocyte functions against bacteria and, hence, it appears to be an attractive agent for infection prophylaxis. It is disappointing that this study failed to demonstrate any prophylactic utility.