Management of fever in neutropenic patients.

Substantial progress has been made in the management of febrile episodes in neutropenic patients, largely by the prompt administration of potent, broad-spectrum antimicrobial agents. During the past several decades, the spectrum of organisms has changed from a predominance of gram-negative pathogens to a predominance of gram-positive pathogens. In recent years, some hospitals have experienced an increase of infections caused by multi-drug-resistant pathogens. Hence, it is no longer possible to rely on standardized regimens, but antimicrobial therapy must be selected based on the predominant pathogens and antimicrobial susceptibility patterns at each institution. It is customary to initiate antifungal therapy empirically in those patients whose fever persists despite broad-spectrum antibacterial therapy. Alternatives now exist to amphotericin B, including lipid formulations of this drug, and fluconazole. It is critically important that each patient be carefully re-assessed before starting antifungal therapy, because there are many other potential causes for persistent fever, including resistant bacteria and viruses. Novel approaches to therapy include outpatient antibiotics, and use of growth factors as adjunctive therapy. There also has been a renewed interest in white blood cell transfusions. Although the prognosis for infection in neutropenic patients has improved greatly, new infectious problems have emerged that limit our successful management of these complications.

Recent experience with Pseudomonas aeruginosa bacteremia in patients with cancer: Retrospective analysis of 245 episodes.

BACKGROUND: Pseudomonas aeruginosa bacteremia is a serious and possibly fatal condition in patients with cancer. OBJECTIVES: To ascertain the frequency, demographics, and predisposing factors for P. aeruginosa bacteremia in patients with cancer and to determine the efficacy of various therapeutic regimens. SUBJECTS AND METHODS: Patient records of the Clinical Microbiology Laboratory, The University of Texas, M. D. Anderson Cancer Center, Houston, were reviewed. From January 1, 1991, through December 31, 1995, 245 eligible cases of P. aeruginosa bacteremia were identified. We examined the patient records for the underlying malignant neoplasm and its management, symptoms and signs of infection, culture results of appropriate specimens, antibiotic therapy, and outcome. We also compared our present experience with a previous analysis from this institution covering the period from January 1, 1972, to December 31, 1981. RESULTS: The incidence of P. aeruginosa bacteremia has decreased compared with the previous study (2.8 vs 4.7 cases per 1000 admissions). It was most common in patients with acute leukemia (55 of 1000 registrations), and the frequency in this disease has not changed. Half of the patients were not in the hospital when they developed their infection. The overall cure rate was 80%, which was a significant (P<.001) increase compared with the 62% cure rate in the previous study. In this study, no significant difference in the cure rates was observed between monotherapy with a beta-lactam and combination therapy overall (P = .72), and in patients with shock (P = 1.0) and those with pneumonia (P = .60). The patients' initial neutrophil counts were not of prognostic value; however, the cure rate depended on subsequent changes in neutrophil count during therapy. CONCLUSIONS: The frequency rate of P. aeruginosa bacteremia has decreased in patients with solid tumors but has remained unchanged in patients with acute leukemia. Antibiotic regimens for empirical therapy of neutropenic patients and especially patients with acute leukemia should still provide coverage against P. aeruginosa.

Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice.

BACKGROUND: Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. METHODS: All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. RESULTS: Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. CONCLUSIONS: Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.

A comparison of aztreonam plus vancomycin and imipenem plus vancomycin as initial therapy for febrile neutropenic cancer patients.

BACKGROUND: The improved efficacy of imipenem over other beta-lactam antibiotics in the treatment of febrile neutropenic patients has been attributed to its broad spectrum of activity. METHODS: A prospective, randomized, clinical trial was performed comparing vancomycin 1 g every 12 hours plus imipenem/cilassatin 500 mg every 6 hours and the same dose of vancomycin plus aztreonam 2 g every 6 hours for empiric treatment of febrile episodes in neutropenic patients with cancer. RESULTS: The imipenem regimen cured 76% of the 148 evaluable episodes compared with a 67% cure rate for the 152 episodes treated with the aztreonam regimen (p = 0.1). Most of the polymicrobial infections (77% or 10/13) treated with the imipenem responded, whereas only 38% (5/13) of these infections responded to the aztreonam regimen. Although the cost of the imipenem regimen was less than the cost of the aztreonam regimen, it was associated significantly more with skin rashes (12/194 vs 3/189, p = 0.02). In a multivariate analysis, a poor outcome was independently associated in both instances with the persistence of neutropenia and the presence of pneumonia (p < 0.001). CONCLUSIONS: Overall, in a multifactorial analysis that included efficacy, toxicity, and cost, the imipenem and aztreonam regimens were comparable.

Low infection rate and long durability of nontunneled silastic catheters. A safe and cost-effective alternative for long-term venous access.

BACKGROUND: Tunneled central venous catheters (CVCs) and infusion ports have often been considered as the only safe alternative for long-term venous access. The objective of this study was to assess the durability, cost, and infection rate of nontunneled, noncuffed Silastic CVCs. METHODS: We studied a representative cohort of 340 consecutive cancer patients with 359 nontunneled Silastic CVCs inserted and followed up at our center. All patients were evaluated clinically and microbiologically at the time of CVC removal. RESULTS: The mean in-place duration of the catheter for the 359 nontunneled CVCs studied was 109 days (total, 39,147 days of catheter use), and the infection rate was 0.13 per 100 catheter days. When compared with the tunneled Hickman catheter, the insertion cost saving was at least $2322 per CVC. At our institution, the use of nontunneled Silastic catheters with the support of an expert infusion team has resulted in an annual cost saving of at least $7,692,000. Long peripheral CVCs (in the basilic/cephalic vein) had a 26% rate of inflammation at the insertion site compared with only 2.6% for the short subclavian CVCs (P < .01). Most of the exit-site inflammations were sterile, with negative skin and catheter cultures. Neutropenia, bone marrow transplantation, high-dose steroids, and use of vesicant chemotherapeutic agents through the CVC did not predispose the patients to catheter infection. By univariate analysis, acute leukemia was the only risk factor for catheter infection. CONCLUSIONS: Given the low infection rate and long durability of nontunneled silicone CVCs, these catheters could offer a cost-effective and safe alternative to surgically implantable tunneled catheters.

Lack of activity of amphotericin B in systemic murine fusarial infection.

Systemic fusarial infections have emerged as a significant cause of mortality in cancer patients. Yet, little is known about the management of these infections. The in vivo antifungal activity of amphotericin B in CF1 mice with disseminated fusarial infections was studied. Two pathogenic strains of Fusarium solani were used. Intraperitoneal administration of amphotericin B in daily doses of 0.5, 1, and 2 mg/kg for less than or equal to 10 days did not prolong survival of treated animals. Clearance of F. solani from kidneys was similar in mice treated with 1 mg/kg per day of amphotericin B and in untreated animals. These results are in agreement with the known in vitro and in vivo resistance of Fusarium species to amphotericin B.

P&T Committee review of fluconazole: an effective alternative to antifungal therapy.

Fluconazole is a new antifungal agent available in both oral and parenteral formulations. According to the experts in this roundtable discussion, fluconazole represents a major clinical advance in the treatment of candidiasis and cryptococcosis in cancer patients, patients with AIDS, organ transplant recipients, and other patients at risk for opportunistic mycoses. The pharmacokinetic profile for fluconazole permits infrequent dosing and also makes it ideal for tissue site infections. Fluconazole's low toxicity gives it an advantage over currently available antifungal therapy and will permit prompt presumptive treatment of selected infections.

Oral ciprofloxacin therapy for infections in cancer patients.

Forty six episodes of infection in 43 cancer patients were treated with oral ciprofloxacin at a dose of 750 mg every 8 h. The overall clinical response was 85%. Patients with microbiologically proven infections had a higher response rate (90%) than patients with infections from whom no causative organism(s) could be isolated (69%). Two of three neutropenic patients responded favourably. Favourable responses were seen in a variety of infections including bacteraemia, urinary tract infection, respiratory tract infection and skin and soft-tissue infection. Resistance to ciprofloxacin developed in one isolate of Pseudomonas aeruginosa. Side effects were mild and were predominantly gastrointestinal in nature. Orally administered ciprofloxacin is safe and effective for the therapy of many serious infections in cancer patients. However, more data are required in patients who are neutropenic.

Comparative in-vitro activity of twenty antimicrobial agents against clinical isolates of Mycobacterium avium complex.

The in-vitro susceptibility of Mycobacterium avium complex isolates, obtained from immunosuppressed patients with and without the Acquired Immunodeficiency Syndrome (AIDS), to various antimicrobial agents was determined. Amikacin, the 4-quinolone compounds--ciprofloxacin, temafloxacin and PD 117558--and the penem SCH 34343 were active against most of the isolates. In-vitro synergism using selected antimicrobial combinations could not be demonstrated. No differences in the susceptibility, depending upon the source of the isolates (AIDS or non-AIDS), were noted.

Cefoperazone plus mezlocillin for empiric therapy of febrile cancer patients.

Two dosing regimens of cefoperazone plus mezlocillin were compared in a prospective, randomized trial for therapy of febrile cancer patients. The two regimens were 5 g mezlocillin plus 2 g cefoperazone intravenously every four hours (higher dose) or 3 g mezlocillin plus 1 g cefoperazone intravenously every four hours (lower dose). Although the overall response rate was higher with the higher dose regimen (78 percent versus 66 percent, p = 0.04), the two regimens were comparable in patients with documented infections (72 percent versus 68 percent). Likewise, the two regimens were equally effective against those infections in which the pathogen could be determined (82 percent versus 82 percent). Serum bactericidal titers of at least 1:32 against a known pathogen were associated with a higher response rate than were titers of less than 1:32, but the higher dose regimen did not result in higher serum bactericidal titers. Hypoprothrombinemia was a side effect, especially with the higher dose regimen, before prophylactic vitamin K was routinely administered to patients. Since there were no major benefits with the use of the higher dose regimen of mezlocillin plus cefoperazone, the lower dose regimen is more appropriate for routine usage.

Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: a prospective randomized study.

Fifty-nine evaluable patients under 65 years of age with measurable metastatic breast cancer and without prior chemotherapy were randomly assigned to treatment with fluorouracil, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (FAC) at standard or high doses (100% to 260% higher than standard FAC) following a dose escalation schedule. Patients randomized to the high-dose FAC received the first three cycles of therapy within a protected environment. Subsequent cycles for this group were administered at standard doses of FAC in an ambulatory setting, the same as for the control group. After reaching 450 mg/m2 of Adriamycin, patients in both groups continued treatment with cyclophosphamide, methotrexate, and fluorouracil until there was disease progression. Analysis of pretreatment patient characteristics showed an even distribution for most known pretreatment factors, although the control group had slightly (but nonsignificantly) more favorable prognostic characteristics. Fourteen patients (24%) achieved a complete remission (CR) and 32 (54%) achieved a partial remission (PR), for an overall major response rate of 78%. There were no differences in overall, CR, or PR rates between the high-dose FAC and control groups. The median response durations were 11 and 10 months for the protected environment and control groups, respectively, and the median survival was 20 months for both groups. Hematologic, gastrointestinal (GI), and infection-related complications were significantly more frequent and severe in the group treated with high-dose chemotherapy. Stomatitis, diarrhea, and skin toxicity were dose-limiting. However, there were no treatment-related deaths. High-dose induction combination chemotherapy with the agents used in this study failed to increase the response rate or survival duration, and resulted in a substantial increase in toxicity.

High-dose induction chemotherapy of metastatic breast cancer in protected environment: a prospective randomized study.

To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.

In vitro evaluation of difloxacin (A-56619), A-56620, and other 4-quinolones against isolates from cancer patients.

The in vitro activity of two new quinolones, difloxacin and A-56620, was compared with that of other quinolones against isolates obtained from bacteremic cancer patients. Both agents had a broad antimicrobial spectrum which included both gram-positive and gram-negative organisms. A-56620 had lower MIC values against most organisms tested than difloxacin, and its activity was comparable to that of ciprofloxacin.

Prophylaxis of oropharyngeal candidiasis with clotrimazole.

A total of 202 evaluable cancer patients were randomly assigned to receive or not receive oral clotrimazole as antifungal prophylaxis during hospitalization. Oropharyngeal candidiasis occurred in 1% of the former patients and 27% of the latter patients (P less than .00001). Candida sp were cultured from the initial throat specimens of 53 control patients and 55 patients who received prophylaxis. Oropharyngeal candidiasis subsequently developed in 2% of the former patients and 38% of the latter patients (P = less than .00001). Oral clotrimazole is an effective agent for prophylaxis of oropharyngeal candidiasis in susceptible cancer patients.

Candidiasis in cancer patients.

Disseminated candidiasis is likely to become an increasing problem in cancer patients. It has occurred in patients undergoing intensive chemotherapy, thermotherapy, and bone marrow transplant. The availability of broad-spectrum cephalosporins with biliary excretion is likely to increase the problem. Although localized candidiasis responds to both topical and parenteral therapy, systemic candidiasis is often fatal, especially in neutropenic patients. A major obstacle to control of this infection is inadequate diagnostic techniques. It is to be hoped that continuing research will yield more effective diagnostic and therapeutic measures.

A randomized study of tobramycin plus ticarcillin, tobramycin plus cephalothin and ticarcillin, or tobramycin plus mezlocillin in the treatment of infection in neutropenic patients with malignancies.

Two hundred twenty-five patients with 358 febrile episodes were treated with tobramycin and ticarcillin (TT), tobramycin and mezlocillin (TM), or tobramycin, ticarcillin and cephalothin (TTC). There were no statistically significant differences in the response rates for patients who were proven to have infection (67% with TT, 69% with TTC and 53% with TM). Patients were more often cured of their infection if their neutrophil count rose during therapy. In this study, the addition of cephalothin to TT did not increase the frequency of azotemia (10% and 12%, respectively). Although mezlocillin has a broader spectrum of activity in vitro than ticarcillin, it was not more efficacious when combined with tobramycin than ticarcillin plus tobramycin for the treatment of infections in neutropenic patients.

Bacteremia caused by a previously unidentified species of rapidly growing Mycobacterium successfully treated with vancomycin.

Bacteremia caused by rapidly growing mycobacteria are usually due to Mycobacterium fortuitum or M. chelonei. Other rapidly growing mycobacteria generally are considered to be nonpathogenic. We report the case of a patient with bacteremia due to an unidentified, rapidly growing, scotochromogenic mycobacteria that was detected by a radiometric blood culture system. Results of in-vitro susceptibility testing indicated that the organism was susceptible to vancomycin and other antimicrobial agents, and the patient was successfully treated with vancomycin. We believe that this is the first report of successful use of vancomycin therapy for a mycobacterial infection.

Cefoperazone for the treatment of infections in patients with cancer.

Cefoperazone was used for the treatment of 105 febrile episodes in 103 patients with cancer. A dose of 12 g/day was administered according to two different schedules, one for neutropenic patients (neutrophil count, less than 1,000/mm3), the other for nonneutropenic patients. The rate of response for 85 episodes of documented infection was 68%. The rates of response for patients with bacteremia and pneumonia were 72% and 41%, respectively; all patients with soft-tissue and urinary-tract infections responded. Fifty-five percent of patients infected with Pseudomonas aeruginosa, the most common gram-negative organism causing infection, responded to therapy. Among patients infected with Staphylococcus aureus, the most common gram-positive organism causing infection, 82% responded. As expected, the rate of response was higher for patients with adequate neutrophil counts. In neutropenic patients the overall response was good, particularly when the neutropenia resolved. However, the occasional occurrence of resistant strains of bacteria precludes the use of cefoperazone alone as initial therapy for neutropenic patients. Toxic adverse reactions, including drug-induced fever, diarrhea, and rash, occurred rarely and were transient. This study indicates that cefoperazone has low toxicity and is effective for the treatment of infections in patients with cancer.