Outpatient antibiotic treatment in low-risk febrile neutropenic cancer patients

Traditionally febrile neutropenic patients have been treated with parenteral antibiotics in an inpatient setting; however, recent work by several investigators has demonstrated successful treatment with both parenteral and oral antibiotics in an ambulatory environment. This has been accomplished by identification of low-risk neutropenic patients, advances in broad-spectrum antibiotics with long half-lives and stabilities, the introduction of the oral quinolones, home health-care initiatives, improvements in vascular access devices, and development of technically enhanced antibiotic delivery systems. Outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients should now be considered an acceptable alternative to hospital-based treatment. This review focuses on the development and rationale of risk stratification and examines the results of various outpatient antibiotic trials recently completed.     

Expanding the Options for Risk-based Therapy in Febrile Neutropenia

Fever in neutropenic cancer patients is often due to the development of an infection. The standard management of febrile neutropenic patients involves the administration of empiric, hospital-based, parenteral antibiotic therapy. Although this treatment strategy has evolved from experience in high-risk patients with hematological malignancies, in whom bacterial infection can result in substantial morbidity and mortality, it has been adopted for all patients with febrile neutropenia, largely because of the inability of clinicians to reliably distinguish between patients who are at high risk for developing such morbidity/mortality and those who are not. The development of risk-assessment models has facilitated the recognition of high-, moderate-, and low-risk subgroups among febrile neutropenic patients and allows the administration of outpatient antibiotic therapy to the moderate- and low-risk groups, with the same degree of efficacy and safety as hospital-based therapy. Monotherapy with the carbapenems (imipenem/cilastatin and meropenem), with their broad spectrum of activity and established efficacy in high-risk patients, represents realistic options for risk-based treatment of febrile neutropenic patients within and outside the hospital setting.     

Vancomycin is not an essential component of the initial empiric treatment regimen for febrile neutropenic patients receiving ceftazidime: a randomized prospective study.

The use of vancomycin as part of the initial antibiotic therapy of febrile neutropenic patients has become a controversial issue. Some studies support its incorporation in the initial regimen, and others suggest that vancomycin can be added later. We examined this issue in a prospective, randomized trial. We randomized 127 febrile neutropenic patients to receive either ceftazidime alone or ceftazidime plus vancomycin as the initial empiric antibiotic treatment. We added vancomycin to the ceftazidime arm of the study when fever persisted after 96 h of monotherapy, when new fever occurred after this time, or when a moderately ceftazidime-resistant gram-positive bacterium was isolated. Each of these regimens had similar initial response rates, similar durations of initial fever, similar frequencies of new fever during therapy, similar microbiological cure rates, similar superinfection rates, and similar survival rates. We observed more renal and cutaneous toxicities in patients receiving vancomycin and ceftazidime as initial therapy. We conclude that ceftazidime is appropriate as initial therapy for febrile neutropenic patients and that the addition of vancomycin is appropriate when fever persists after 4 days of monotherapy or when fever recurs following an initial response.     

Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin as empiric therapy for fever in severely neutropenic patients

The objective of this trial was to evaluate the potential advantages of the combination of piperacillin and tazobactam in the control of fever in neutropenic patients. In this single-center study, patients who experienced a total of 247 febrile episodes were prospectively randomized to receive either our standard regimen, ceftazidime 3 g/day (1 g t.i.d.) plus tobramycin 3 mg/kg per day (1.5 mg/kg b.i.d.), or piperacillin 12 g/day plus tazobactam 1.5 g/day (4 g+0.5 g t.i.d.) plus tobramycin 3 mg/kg per day (1.5 mg/kg b.i.d.). Vancomycin was added in all cases of persistent fever in the ceftazidime arm, but only when there was microbiologically documented resistance in the piperacillin/tazobactam arm. All 247 episodes were evaluable by "intent-to-treat" analysis. The two populations were well matched in terms of age, gender, underlying disease, chemotherapy received, oral decontamination, clinical and bacterial documentation, and severity and duration of neutropenia. Initial antibacterial therapy was successful (apyrexia at 72 h, without antibiotic change) more frequently (P=0.008) with the regimen containing piperacillin/tazobactam (54.4%) than with the one including ceftazidime (37.6%). Fewer (P=0.02) major infectious events (infectious death or delay in treatment of underlying disease due to infection) were observed during piperacillin/ tazobactam treatment (2.6%) than with the ceftazidime regimen (11.3%), despite a lower frequency of glycopeptide addition when piperacillin/tazobactam was used (54.4% versus 77.4%) according to the rules adopted. This trial confirmed the efficacy of the piperacillin/tazobactam combination for empirical treatment of febrile neutropenic patients. This antibiotic combination permitted a dramatic decrease in empiric glycopeptide antibiotic administration in such patients. Electronic publication: 12 January 1999     

Comparison of cefepime versus ceftriaxone-amikacin as empirical regimens for the treatment of febrile neutropenia in acute leukemia patients

BACKGROUND: High-intensity regimes of chemotherapy have led to longer and more severe episodes of neutropenia with a resulting increase in morbidity and mortality due to infections. Which empiric antibiotic regimen to use in these cases is still under debate. METHODS: We performed a randomized comparative study to evaluate the efficacy of cefepime versus ceftriaxone plus amikacin as the initial treatment in an escalating, empirical, antibiotic therapy regimen in febrile neutropenic patients. Both adults and children were included. All patients had less than 500 neutrophils/microl at the time of infection. Patients were randomized to receive either cefepime or ceftriaxone plus amikacin. If infection continued 72 h later, patients in both groups received vancomycin, and if infection had not disappeared 7 days after starting antibiotics, amphotericin B was started. RESULTS: Twenty patients were included in each group. Both treatment and control groups were comparable for age and sex, among other factors. There were 18 cures in the cefepime group and 17 in the ceftriaxone plus amikacin group (p = 0.9). No patient discontinued therapy because of toxicity. CONCLUSIONS: Cefepime is a safe and very effective therapy for patients with acute leukemia and febrile neutropenia; in addition, it is a cheaper regimen in our country, and lacks the potential toxicity of the aminoglycosides.     

Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

Gram-positive bacteria have become the predominant infecting organisms in granulocytopenic cancer patients. Empiric antibiotic regimens used in febrile neutropenic patients often include an extended-spectrum cephalosporin, but the response to therapy in gram-positive coccal bacteremia has been unsatisfactory. Thus, new antibiotics with better activity against gram-positive bacteria should be tested. The objective of this prospective randomized controlled study was to evaluate and compare the efficacy and tolerance of piperacillintazobactam plus amikacin with that of ceftazidime plus amikacin, the standard regimen of the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer, in the empiric treatment of febrile granulocytopenic cancer patients. A total of 858 episodes were eligible for this study, and 706 episodes were assessable for efficacy. The antibiotic treatment was successful in 210 (61%) of 342 episodes in the piperacillin-tazobactam-amikacin group compared with 196 (54%) of 364 episodes treated with ceftazidime plus amikacin (P = 0.05). The time to defervescence was significantly shorter (P = 0.01) and the time to failure was significantly longer (P = 0.02) in the piperacillin-tazobactam-amikacin group. A significant difference in response to bacteremic infections between the two patient groups was found: piperacillin-tazobactam plus amikacin was successful in 40 of 80 episodes (50%), and ceftazidime plus amikacin was successful in 35 of 101 episodes (35%) (P = 0.05). A multivariate analysis showed that the probability of failure was significantly greater with ceftazidime plus amikacin than with piperacillin-tazobactam plus amikacin (P = 0.02). This trial suggests that piperacillin-tazobactam plus amikacin is more effective than ceftazidime plus amikacin for the empiric treatment of fever and bacteremia in granulocytopenic cancer patients. Although cutaneous reaction was more frequently associated with piperacillin-tazobactam plus amikacin than with ceftazidime-amikacin, this unwanted effect was relatively mild and its incidence was comparable to that of other penicillin compounds.     

A comparative study of cefepime versus ceftazidime as empiric therapy of febrile episodes in neutropenic patients.

An open-label, randomized comparative study was conducted to evaluate the efficacy and safety of cefepime (2.0 g q. 8 h) and ceftazidime (2.0 g q. 8 h) in the empiric therapy of febrile neutropenic patients. A total of 45 eligible febrile episodes were randomized (1:1) to be treated with the study regimen. Nineteen febrile episodes treated with cefepime and 22 febrile episodes treated with ceftazidime were evaluable for efficacy. The two groups were comparable in terms of age, sex, height, weight, underlying neoplasm, number of pretherapy neutrophil, duration of neutropenia and types of infections. The overall therapeutic success rate of the cefepime group (53%) was comparable to the ceftazidime group (50%). It did not differ significantly (95% confidence interval: -0.28 to 0. 34, p = 0.85). Eighty-eight percent of pathogens in each group were bacteriologically eradicated. The safety profile was similar in both groups. No patients in either group discontinued the therapy because of adverse events. None (0%) of the cefepime patients and 2 (9%) of the ceftazidime patients died of infection. The results of this study suggest that cefepime is an effective and safe agent in the empiric therapy of febrile episodes in neutropenic patients.     

Procalcitonin – a sensitive inflammation marker of febrile episodes in neutropenic children with cancer

Objective Sensitive parameters of inflammations, are rare or of limited validity in neutropenic patients. Procalcitonin (PCT) proven to be a sensitive inflammatory marker in nonneutropenic patients was evaluated for its diagnostic relevance in febrile episodes of neutropenic patients with cancer Methods Plasma levels of PCT were determined by an immunoluminometric assay in children with febrile neutropenic episodes (n=376) starting at the date of admission until the resolution of fever and were correlated with serum levels of the C-reactive protein (CrP). Febrile episodes were classified as fever of unknown origin (FUO), microbiologically or clinically documented infections and were also differentiated according to the site of the infection (unknown, bacteremia, respiratory, soft tissue, gastrointestinal and urinary tract infection). Results Independently from the aetiology and the site of infection the PCT peak value occurred mostly on the second hospital day and decreased rapidly in cases of successful antibiotic therapy and with the resolution of fever to the normal range (0.1–0.5 μg/l). The highest PCT peak levels at the onset of fever and during the febrile course were observed in patients with gramnegative bacteremia (n=22, median 12.1 μg/l, range 0.4–568.2 μg/l). There was a positive correlation between PCT peak levels and CrP peak levels (r=0.48, p=0.001) which mostly were observed 24 h later than for PCT. Conclusions PCT is a sensitive and specific parameter in the diagnostic and in the sequential assessment of febrile neutropenic episodes, especially in gramnegative infections. Its diagnostic accuracy in neutropenic patients is clearly higher than that of CrP.     

Response rates to a staged antibiotic regimen in febrile neutropenic patients

In a prospective study of 50 patients with prolonged neutropenia, we observed a 75% response rate to a staged empirical antibiotic regimen used to treat 101 episodes of fever. Additions or modifications to the protocol were rarely necessary. The use of an approach such as this improves the management of febrile neutropenic patients.     

Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients

Between July 1993 and September 1996, 107 consecutive febrile episodes in 83 neutropenic cancer patients with a median age of 41 years were randomized to treatment either with piperacillin/tazobactam 4.5 g every 8 h i.v. or ceftazidime 2 g every 8 h plus amikacin 15 mg/kg i.v. per day. In the case of fever >38° C 48 h after initiation of the antibiotic therapy, vancomycin 500 mg every 6 h i.v. was added. The study population was at serious risk of a poor outcome, since 67% of the patients had leukemia or lymphoma, 19% of the febrile events occurred after autologous bone marrow or blood stem cell transplantation, the median total duration of neutropenia was 16 days, and the median neutrophil count at study inclusion was 0.09 × 10⁹/l. The two patient groups were comparable in terms of risk factors. Bacteremia was found in 37%, other microscopically documented infections in 16%, and clinically documented infections in 26% of the febrile episodes. Most (96) febrile episodes were evaluable for response. No significant difference was found between piperacillin/ tazobactam and ceftazidime plus amikacin in terms of success rate (81% versus 83%), empirical addition of vancomycin (42% versus 38%), median time to fever defervescence (3.3 versus 2.9 days) or median duration of antibiotic therapy (7.2 versus 7.4 days). No patient died from the infection. Both antibiotic regimens were well tolerated, the study treatment being stopped only in 1 patient because of toxicity (cutaneous allergy to piperacillin/tazobactam). On the basis of the 107 febrile events encountered, we conclude that piperacillin/tazobactam is a safe and effective monotherapy. To define the definitive value of piperacillin/ tazobactam as a monotherapy for febrile neutropenic patients a large randomized trial is warranted.     

Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score

Objective The objective of this study was to prospectively validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score in an attempt to accurately predict on presentation with febrile neutropenia those cancer patients who are at low- or high-risk for development of serious medical complications during the episode.Patients and methods Patients who presented with febrile neutropenia during November 2000 and July 2002 were prospectively enrolled in the protocol. All patients were hospitalized until recovery or outcome of the event and were treated with broad-spectrum, empiric, intravenous antibiotic therapy. The MASCC risk-index score (based on seven independent factors present at onset of febrile neutropenia) was calculated in 64 patients with 80 febrile neutropenic episodes. Patients with a score of 21 were regarded as low risk; patients with a score of <21 were regarded as high risk.Results Of the 80 febrile neutropenic episodes, 58 were classified as low-risk and 22 as high-risk patients. Fifty-seven (98.3%) of the 58 low-risk patients recovered without complications, and three (13.6%) of the 22 high-risk patients did not develop medical complications. One low-risk patient developed a fungal infection but recovered completely in comparison to 11 high-risk patients (50%) who developed serious medical complications (p<0.001). None of the low-risk patients died. However, eight (36.4%) of the 22 high-risk patients died during the febrile neutropenic episode (p<0.001), six as a consequence of sepsis and two due to rapidly uncontrolled cancer.Conclusion We correctly predicted 98.3% of low-risk patients and 86.3% of high-risk patients. This study had a positive predictive value of 98.3% and a negative predictive value of 86.4% with both a sensitivity and specificity of 95%. The MASCC risk-index score correctly identifies low- and high-risk patients at presentation with febrile neutropenia.     

Procalcitonin - a sensitive inflammation marker of febrile episodes in neutropenic children with cancer

Objective: Sensitive parameters of inflammations are rare or of limited validity in neutropenic patients. Procalcitonin (PCT) proven to be a sensitive inflammatory marker in nonneutropenic patients was evaluated for its diagnostic relevance in febrile episodes of neutropenic patients with cancer.¶Methods: Plasma levels of PCT were determined by an immunoluminometric assay in children with febrile neutropenic episodes (n = 376) starting at the date of admission until the resolution of fever and were correlated with serum levels of the C-reactive protein (CrP). Febrile episodes were classified as fever of unknown origin (FUO), microbiologically or clinically documented infections and were also differentiated according to the site of the infection (unknown, bacteremia, respiratory, soft tissue, gastrointestinal and urinary tract infection).¶Results: Independently from the aetiology and the site of infection the PCT peak value occurred mostly on the second hospital day and decreased rapidly in cases of successful antibiotic therapy and with the resolution of fever to the normal range (0.1-0.5 wg/l). The highest PCT peak levels at the onset of fever and during the febrile course were observed in patients with gramnegative bacteremia (n = 22, median 12.1 wg/l, range 0.4-568.2 wg/l). There was a positive correlation between PCT peak levels and CrP peak levels (r = 0.48, p = 0.001) which mostly were observed 24 h later than for PCT.¶Conclusions: PCT is a sensitive and specific parameter in the diagnostic and in the sequential assessment of febrile neutropenic episodes, especially in gramnegative infections. Its diagnostic accuracy in neutropenic patients is clearly higher than that of CrP.     

Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open,randomized, multicentre trial

BACKGROUND: Standard therapy for suspected infections in patients with profound neutropenia is the combination of a beta-lactam antibiotic plus an aminoglycoside. Cefepime's broad-spectrum activity makes it an option for initial empirical therapy in neutropenic patients. The aim of this study is to evaluate the efficacy and safety of cefepime plus amikacin compared with piperacillin-tazobactam plus amikacin for initial empirical treatment of fever in adult haematology patients with severe neutropenia. METHODS: In this prospective multicentre trial, 969 patients with 984 febrile neutropenic episodes were randomized to receive iv amikacin (20 mg/kg every 24 h) combined with either cefepime (2 g every 8 h) or piperacillin-tazobactam (4 g/500 mg every 6 h). Clinical response was determined at 72 h and at completion of therapy. RESULTS: Eight hundred and sixty-seven episodes were assessable for efficacy (432 cefepime, 435 piperacillin-tazobactam). The frequency of success without modification of the empirical therapy was nearly identical for cefepime plus amikacin (49%) compared with piperacillin-tazobactam plus amikacin (51%). Similar rates of success were found for microbiologically documented infection: 40% versus 39%, respectively. Antibiotic modification was necessary in 49% of cefepime and 44% of piperacillin-tazobactam patients. The overall response rate, with or without modification of the assigned treatment, was 94% in both groups. Drug-related adverse events were reported in 10% of cefepime plus amikacin versus 11% of piperacillin-tazobactam plus amikacin patients. Mortality due to infection occurred in a total of 10 patients (two cefepime, eight piperacillin-tazobactam). CONCLUSION: The empirical regimen of cefepime plus amikacin is equivalent to piperacillin-tazobactam plus amikacin in febrile adult haematology patients with severe neutropenia. Keywords: cefepime, piperacillin-tazobactam, amikacin, empirical antibiotic therapy, febrile neutropenia, haematological malignancy     

Outpatient management of febrile episodes in neutropenic cancer patients

Febrile neutropenic patients have traditionally received hospital-based parenteral antibiotic therapy because of the risk of serious complications and associated mortality. Recently a low-risk subset among febrile neutropenic patients has been identified. Several alternatives to hospital-based therapy have been evaluated in such patients. These include early discharge to home antibiotic therapy after initial stabilization in the hospital, or treatment of the entire febrile episode with intravenous and/or oral antibiotics in an ambulatory setting. A multidisciplinary approach involving the physician and other health-care providers, the patients, and their families, ensures the success of this therapeutic modality. Careful patient selection, daily follow-up, close monitoring for the development of complications and/or adverse reactions, and informed consent along with detailed instructions to patients, minimize the risk of the development of serious complications. Outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients should now be considered an acceptable alternative to hospital-based therapy.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

Prospective randomized comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenic patients.

The standard regimen used by members of the European Organization for Research on Treatment of Cancer Antimicrobial Therapy Cooperative Group for empiric therapy of febrile neutropenic cancer patients has been treatment with ticarcillin plus amikacin. A three-arm prospective randomized controlled trial was performed to determine whether the extended-spectrum antipseudomonal penicillin azlocillin or the extended-spectrum cephalosporin cefotaxime had more or less efficacy than the beta-lactam in the ticarcillin-plus-amikacin regimen. A total of 742 patients from 22 institutions were evaluated. Single gram-negative rod bacteremias accounted for 83 episodes, and it was among these patients that the prognosis was least satisfactory, leading to a more intensive evaluation of this patient group. In these patients the azlocillin-plus-amikacin regimen resulted in a 66% response rate, compared with a 37% response rate for patients who received cefotaxime plus amikacin (P = 0.080) and a 47% response rate for patients who received ticarcillin plus amikacin (P = 0.207). The patients with gram-negative rod bacteremias and persistently profound granulocytopenia had substantially poorer response rates (37%) than the patients with rising granulocyte counts (73%; P = 0.004). A logistic regression analysis indicated that the following factors also affected infection resolution: beta-lactam utilization in the regimen (azlocillin was better than ticarcillin or cefotaxime), resolution of profound granulocytopenia (less than 100 cells per microliter) during therapy, and susceptibility to the beta-lactam antibiotic.     

Outcomes of treatment pathways in outpatient treatment of low risk febrile neutropenic cancer patients

Background We treated low-risk febrile neutropenic cancer patients utilizing two standard outpatient antibiotic pathways: oral ampicillin/clavulanate (500 mg) and ciprofloxacin (500 mg) or intravenous ceftazidime (2 g) and clindamycin (600 mg) every 8 h. The objectives were to determine the success of outpatient treatment of low-risk febrile neutropenia, to identify factors predicting outpatient failure, and to determine mortality related to the febrile episode.Methods Eligibility criteria included solid tumor diagnosis, stable vital signs, temperature 38.0°C, absolute neutrophil count (ANC) of <1000/ml, patient compliance, no significant organ dysfunction, ability to tolerate oral medication and fluids for oral pathway, residence within 30 miles of the institution, 24-h caregiver, and telephone and transportation access.Results There were 257 febrile episodes in 191 patients meeting the criteria. Patients were treated during March 1998 through February 2000. Median age was 48 (range, 17–77) years, and 60% (n=153) had an entry ANC of <100/ml; 205 (80%) febrile episodes successfully responded to outpatient treatment, and 52 (20%) were hospitalized. Logistic regression analysis showed the following were related to hospitalization: mucositis >grade 2 (p <0.002); Zubrod performance status 2 (p=0.029); ANC <100/ml (p=0.039), and age 70 years (p=0.048).Conclusions Outpatient treatment of low-risk febrile neutropenic cancer patients utilizing standard treatment pathways is associated with minimal morbidity and mortality and should be considered an acceptable standard of care with appropriate infrastructure available to provide strict and careful follow-up while on treatment. Certain factors are associated with higher risk of hospitalization and should be further examined in eligible patients with low-risk febrile neutropenia.Presented at the 2002 American Society of Clinical Oncology, Orlando, Florida, USA.     

Tobramycin once versus three times daily, given with penicillin G, to febrile neutropenic cancer patients in Norway: a prospective, randomized, multicentre trial

OBJECTIVES: Penicillin G with an aminoglycoside is the standard initial empirical treatment in febrile neutropenia in Norway. It has been argued that giving the aminoglycoside once daily to neutropenic patients with Gram-negative bacteraemia may be hazardous when penicillin G is the beta-lactam antibiotic. We questioned this argument and hypothesized that tobramycin once daily was as efficacious as three times daily. METHODS: We conducted a randomized prospective multicentre study, comparing the efficacy of tobramycin 6 mg/kg once (arm A) versus three times (arm B) daily, plus penicillin G 5 million IU x 4, in febrile neutropenic cancer patients. Primary outcome: modification of the antibiotic regimen. RESULTS: One hundred and seventy-four patients were evaluable for intention-to-treat analyses. One hundred and fifty-five patients had lymphoma or leukaemia as the underlying cancer diagnosis. In arm A, 35 of 88 patients and in arm B, 34 of 86 patients, that is 40% in both arms had no modification of the antibiotic regimen. No patients died while participating in the study. Upon modification of the antibiotic regimen, all patients were successfully treated. The increase in serum creatinine was modest and similar in the two treatment groups. CONCLUSIONS: When administered with penicillin G, tobramycin given once daily was as efficacious and safe as tobramycin given three times daily in cancer patients with febrile neutropenia in Norway, provided the regimen was modified according to the clinical response.     

Prospective randomized clinical trial of teicoplanin for empiric combined antibiotic therapy in febrile, granulocytopenic acute leukemia patients.

The increasing prevalence of bacteremia caused by gram-positive bacteria in granulocytopenic acute leukemia patients prompted us to evaluate, in a prospective randomized trial, the role of teicoplanin, a new glycopeptide antibiotic, when it was added to amikacin plus ceftazidime, as an empiric therapy of fever in these patients. Of 47 evaluable episodes, 22 were treated with the teicoplanin regimen and 25 were treated with the combination of amikacin and ceftazidime. The overall response to therapy of patients treated with teicoplanin was slightly better (82% improvement) than that obtained with amikacin plus ceftazidime (52%). The response rate of patients with gram-positive bacteremias was 80% (4 of 5) to the regimen that included teicoplanin; 25% (1 of 4) of the patients treated with amikacin plus ceftazidime responded to treatment; and for patients with gram-negative bacteremias, the response rates were, respectively, 100% (4 of 4) and 70% (7 of 10). The better results obtained with amikacin-ceftazidime-teicoplanin treatment were most evident in patients with profound (less than 100/mm3) and persistent neutropenia (83 versus 30% improvement). Furthermore, a good response rate of patients with gram-positive bacteremias (seven of eight; 87% improvement) was achieved in a small group of bone marrow transplant patients who were all treated with amikacin-ceftazidime-teicoplanin. No severe side effects were documented in any patient. Teicoplanin, as a drug administered as a single daily dose, seems to be a safe and useful anti-gram-positive agent when used in combination with amikacin-ceftazidime as an empiric therapy of febrile episodes in granulocytopenic acute leukemia patients.     

Randomized prospective study of ceftazidime versus ceftazidime plus cephalothin in empiric treatment of febrile episodes in severely neutropenic patients.

In a prospective randomized study, ceftazidime monotherapy was compared with a combination of ceftazidime plus cephalothin in 102 febrile neutropenic patients. Thirty bacteriologically documented infections, of which 23 were bacteremias, in 48 clinically assessable patients were treated with ceftazidime alone. Twenty-four bacteriologically proven infections, of which 18 were bacteremias, in 42 clinically assessable patients were treated with a combination of ceftazidime and cephalothin. The clinical response rates in assessable patients were 77% for ceftazidime monotherapy and 88% for the combination. The bacteriological clearance rate was 70% for ceftazidime monotherapy and 79% for the combination. Efficacy against gram-negative pathogens appeared to be excellent, with 93% clearance for ceftazidime monotherapy and 100% clearance for the combination. The bacteriological clearance of gram-positive infections was only 60% for both regimens, with failures mainly due to Streptococcus faecalis and Streptococcus sanguis, which are primarily resistant to both ceftazidime and cephalothin. After addition of vancomycin to those infections which did not respond to empiric therapy, bacteriological clearance rates of 94% (ceftazidime plus vancomycin) and 90% (ceftazidime and cephalothin plus vancomycin) were achieved. Three superinfections were registered in the ceftazidime group and two were seen in the combination group. Other adverse effects of ceftazidime were minimal and were not enhanced by combination with cephalothin. It is concluded that ceftazidime is an effective drug for the empiric treatment of febrile neutropenic patients, especially if one is prepared to modify therapy if resistant gram-positive strains or mycotic infections are encountered. Neither the clinical nor bacteriological cure rates could be substantially improved by adding cephalothin to ceftazidime in initial empiric treatment of febrile neutropenic patients.     

Gentamicin and low dose piperacillin in febrile neutropenic patients

One hundred and twenty-seven febrile neutropenic patients were randomized to receive empirical antibiotic therapy with intravenous gentamicin and 12 g/day or 8 g/day piperacillin. Despite a high incidence of Hickman catheter infections by antibiotic-resistant bacteria, there was an overall response in 56% of patients and no difference in the numbers responding to each antibiotic regimen. In addition, the duration of fever was not significantly different in the two groups of patients. The majority of the unresponsive patients responded to the addition of further antibiotics and there were only two infection related deaths. The results suggest that high dose antibiotics are not essential for the initial empirical therapy in febrile neutropenic patients.