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Imipenem/Cilastatin Versus Piperacillin/Tazobactam Plus Amikacin for Empirical Therapy in Febrile Neutropenic Patients: Results of the COSTINE Study*

Posted on: Saturday, 11 June 2005, 03:00 CDT

Key words: Amikacin - Fever - Imipenem - Neutropenia - Piperacillin/tazobactam

ABSTRACT

Background: Combinations of beta-lactams plus aminoglycosides have become standard therapy for suspected infections in patients with profound neutropenia. However, it is not clear whether such combinations are advantageous over therapy with a broad-spectrum antibiotic.

Objective: To assess the clinical effectiveness and the cost- effectiveness ratio of empirical therapy of febrile neutropenia with imipenem/ cilastatin (I/C) versus piperacillin/tazobactam plus amikacin (P/T+A).

Research design and methods: Prospective, multicenter observational study with 2 matched parallel cohorts treated with I/ C (500mg/6h iv) or P/T+A (P/T: 4g/6h iv; A: 20mg/kg/day iv).

Main outcome measures: Therapeutic success was defined as the resolution of fever following ≥ 7 days of unchanged antibiotic treatment. An economic comparison was conducted focusing on the daily treatment costs, and the management of its toxicity.

Results: There were 343 eligible patients (180 I/C, 163 P/T+A), of whom 290 were evaluable for the primary clinical effectiveness analysis. Followup information beyond 7 days of study inclusion was only available for 52% of all evaluable patients. Treatment success was observed in 42% of I/C patients compared with 31 % of P/T+A patients (95% CI: -0.01, 21.4). The incidence of drug-related adverse experiences was 13% for I/C and 6% for P/T+A, with no differences in moderate or severe adverse experiences nor in those causing discontinuation of antibiotic therapy. Treatment costs were 189.55 euros (95% CI: 127.46-251.46) lower per episode of febrile neutropenia for patients treated with I/C.

Conclusions: The clinical effectiveness of I/C was similar to that of P/T+A. In both treatment groups toxicity was low and did not limit antibiotic therapy. Resource consumption was lower with I/C.

Introduction

Cancer patients who become neutropenic following myelosuppresive chemotherapy are at high risk of developing severe infections, which may cause significant morbidity and mortality1. For many years, combinations of beta-lactams and aminoglycosides have been standard therapy for suspected infections in neutropenic patients2. Addition of aminoglycosides was thought to provide synergistic bacterial killing and significant antipseudomonal activity, while minimizing the appearance of resistances during treatment3-6. Moreover, the usefulness of aminoglycosides in neutropenic patients has been documented in Gram-negative sepsis7,8. More recently, in a clinical trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) piperacillin/tazobactam plus amikacin (P/ T+A) was found to be more effective than ceftazidime plus amikacin for the empirical treatment of febrile granulocytopenic patients with cancer9.

The advent of new broad-spectrum bactericidal antibiotics has offered the prospect of single-agent therapy. One recent meta- analysis10 concluded that monotherapy may be as effective as aminoglycosidecontaining combinations for empirical treatment of febrile neutropenia. Imipenem is a type II carbapenem with excellent microbiological activity against both Gram-negative (including ESBL- producing microorganisms) and Gram-positive bacteria11. For clinical use it must be co-administered with cilastatin, a renal dehidropeptidase-1 inhibitor, so as to be able to avoid its rapid degradation by this enzyme which is found in the proximal renal tubules of mammals12'13. Several studies have demonstrated the effectiveness of I/C, either alone or as part of combination therapy, for empirical treatment of febrile neutropenic episodes14- 22. Based on its broad spectrum activity and efficacy record, I/C represents a good alternative to combinations of beta-lactams and aminoglycosides23.

The present study was a prospective, multicenter, observational clinical study to assess the effectiveness, the safety, and the therapeutic costs of I/C compared with P/T+A for the empirical treatment of fever in patients with hematological malignancies and severe neutropenia.

Patients and methods

Patient eligibility

In this comparative, multicenter, observational clinical study, 13 Spanish institutions took part. The study was designed and conducted in accordance with the Good Clinical Practices issued by the International Conference of Harmonization (ICH) and all applicable national and local regulations, and was approved by the Ethics Review Committee of Hospital Clnic i Provincial (Barcelona, Spain).

Eligible patients older than 18 years included those who received myelosuppresive chemotherapy for hematological malignancy or had undergone hemopoietic stem cell transplantation. Hospitalized patients were eligible for study participation if they had fever (> 38.3C on one occasion or ≥ 38.0C for longer than 1 hour), neutropenia (absolute neutrophil count of < 500 cells/l or of < 1000 cells/l expected to fall below 500 cells/l within 24 to 48 hours), and a presumed infection. All patients were informed about the investigative nature of this study and provided informed consent.

Patients were excluded from the observational study if they had received any intravenous antibiotic during the 96 hours prior to study inclusion, had been previously included in this protocol or had received treatment with any investigational drug within the preceding 3 months, had renal failure requiring hemo- or peritoneal dialysis or a serum creatinine level of > 200mol/l or an estimated creatinine clearance of < 20ml/min, were pregnant or nursing mothers, had a concomitant documented invasive fungal infection, had a Karnofsky score of < 30 or were not expected to survive at least 48 hours, or had known human immunodeficiency virus (HIV) infection.

Hypothesis and sample size calculation

The primary objective of this prospective, cohort (double group), observational study was to compare the clinical effectiveness and the cost of 2 empirical antibiotic regimens in febrile neutropenic patients (see below). Additional secondary objectives included comparisons of the 2 treatment arms with respect to microbiological effectiveness, incidence of breakthrough infections, survival, relapse rates, duration of neutropenia, and time to fever resolution and recovery of neutropenia.

According to a meta-analysis of clinical studies of imipenem/ cilastatin for empirically treating febrile neutropenic patients24, the expected overall response rate to I/C was 55% among all evaluable patients. To detect an absolute increment of 15% for the overall response rate in the I/C arm with respect to the P/T+A arm, with a one-tailed test with a type I error level of 5% and a power in excess of 80%, 196 evaluable patients had to be included in each treatment arm.

Similarly, we estimated that the study sample size would be sufficient to demonstrate statistically significant differences (of ≥ 2 days) of time to resolution of fever, and length of neutropenia and hospital admission, under the assumption that standard deviations for those variables would be [asymptotically =] 5 days. The sample size would also be sufficient to demonstrate a difference of 15% between the proportions of feverless patients 72 hours after the onset of antibiotic therapy in both study arms. Lastly, the sample size would also allow for the detection of differences of ≥ 20% in the proportion of patients who used a specific medical resource, under the assumption that ≥ 5% of the evaluable patients did so.

Therapeutic regimens

Since this study was observational in nature, the choice of treatment administered to eligible patients was determined by their corresponding treating physicians based solely on clinical criteria. None of the study drugs was provided free of charge to the hospitals by the study sponsor, Merck Sharp & Dohme of Spain.

Patients received either intravenous I/C (500 mg every 6 hours, infused over a period of 20 to 30 minutes) or P/T+A (P/T: 4g/500mg every 6 hours, infused over a period of 20 to 30 minutes; A: 500 mg every 12 hours, infused over a period of 30 to 60 minutes). For adults with impaired renal function, appropriate reductions in dose administered of both study drug regimens had to be made.

Monitoring of the levels of the study antibiotics was not required by the protocol, yet it was performed as clinically indicated. In most sites, commercially available assays were used to determine peak and trough levels of antibiotics. Doses of antibiotics were adjusted accordingly.

Clinical and laboratory evaluation

Complete medical histories were taken and physical examinations, involving routine chest X-rays as well as results of a complete battery of laboratory tests. These included haematology, chemistry, and more than 2 sets of blood cultures (from different venipunctures), which were collected for all patients prior to initiating study antibiotics (Visit 1). Other cultures were performed as clinically indicated.

Patients were monitored daily for clinical signs and symptoms and intercurrent events during antibiotic treatment. Results of complete blood cell counts, coagulation, and chemistry parameters were collected 72 hours after the onset of study therapy (Visit 2), and there\after on Days 4 (Visit 3), 7 (Visit 4), and 14 (Visit 5). Microbiological specimens were obtained before and during study therapy, as clinically indicated. Other procedures (e.g. fibrobronchoscopy, biopsies, etc) were performed in patients with suspected infection as clinically indicated. Data on in vitro susceptibility to I/C, P/T, and A was collected for all bacterial isolates obtained. Due to the observational nature of this study, no specific methodology for susceptibility testing was recommended by the protocol; nonetheless, most microbiology laboratories at the sites participating in this study determined MIC values as recommended by the NCCLS25.

Classification of febrile episodes and evaluation of response

Primary febrile episodes were classified as: (i) microbiologically documented infections with or without bacteremia; or (ii) clinically documented infections (including unexplained fever and noninfectious fever unknown to the treating physician at onset of empirical antibiotic therapy). Single blood culture isolates were sufficient to classify an episode as bacteremic, except for coagulase-negative staphylococci and Corynebacterium spp. other than Corynebacterium jeikeium, which required ≥ 2 positive blood culture specimens2,26.

Response was assessed in each study visit, with an overall evaluation 7 days after the onset of empirical antibiotic therapy (Visit 4). Successful response to therapy in evaluable patients required that they received antibiotics for a minimum of 7 days. A patient's response was defined as a success if fever and clinical signs of infection (whenever present) resolved and if the infecting microorganisms (whenever isolated) were eradicated without any changes in the initially prescribed antibiotic therapy. The return to a normal temperature (< 38C) had to be maintained for at least 4 consecutive days to qualify as treatment success. In addition to this, the primary infection could not have recurred within 1 week after discontinuation of study therapy.

A patient's response was defined as a failure if (i) the patient died during the study follow-up period and because of the primary infection; (ii) persistence of the primary infection or documentation of a breakthrough bacterial infection during study therapy; or (iii) any modification (addition or substitution) of the empirical antibiotic regimen prompted by clinical refractoriness or in vitro resistance to study therapy of the documented pathogen (s). Persistence of fever was considered a cause for failure only after 72 hours of the study therapeutic regimen.

A patient's response was considered nonevaluable for response to study therapy if (i) a coexistent fungal or viral infection was diagnosed; (ii) the febrile episode was clearly not related to infection; or (iii) a protocol violation precluded evaluation of the patient's response.

Therapeutic costs were estimated prospectively from the hospital perspective, including resources used during empirical antibiotic therapy and subsequent follow-up as defined by the protocol. The primary endpoint was the cost per episode of febrile neutropenia treated. The study was conducted from the perspective of the Spanish National Health Insurance funds and focused on the daily management costs, including the cost of antibacterials and the cost of managing adverse events. All costs were valued in 2002 euros, and unit cost data were obtained from a health economic evaluation database updated through 2002 (SOIKOS, Barcelona, Spain). This database contains references to both health costs and fees; following the recommendations of the Canadian Coordinating Office for Health Technology Assessment27, costs were generally preferred over fees for the costing process.

Toxicity

Patients were monitored for clinical and laboratory adverse experiences possibly, probably or definitely related to study antibiotic regimens based on the treating physician's clinical judgment. For this purpose, standard definitions of adverse experiences were used. Clinical adverse experiences were determined by the investigator. Results from periodic laboratory tests were reviewed by the investigators to determine if abnormal findings should be classified as laboratory adverse experiences.

When adverse experiences were identified, the investigator assessed the seriousness of the event and its causal relationship to the study drug. Investigators also recorded whether the adverse experience resulted in discontinuation of therapy. Any adverse experience judged even possibly related to any of the study drugs was designated as 'drug-related'. Adverse experiences were graded according to the World Health Organization (WHO) grading system28. Specifically, nephrotoxicity was defined as an increase in serum creatinine levels of 50% or more over baseline values, or peak greater than 45mol/l. Hepatotoxicity was defined as an increase of serum aminotransferases (AST, ALT) or bilirubin or alkaline phosphatase 1.5 times above baseline values and normal ranges.

In those patients who died during or following empirical antibiotic therapy, an assessment of causality was made to determine whether or not death was related to study treatment regimens. Death was attributed to infection when it was the direct consequence of the primary infectious episode or a breakthrough infection.

In any case, study-oriented assessment of adverse experiences by the investigators was not meant to interfere with their reporting to the local pharmacovigilance authorities through the standard procedures.

Statistical analysis

All case report forms were reviewed for completeness, accuracy, eligibility criteria, and assessment of the outcome variables. All data were entered into a computerized database and analyzed by using the SPSS for Windows v. 11.0 software package (SPSS Inc., Chicago, Illinois, USA).

Demographic data and baseline clinical characteristics of eligible patients were first compared between treatment groups by chi-square testing. Also, in trying to identify selection biases that may influence outcome, baseline characteristics of patients lost to follow-up within each treatment group were also compared.

For the clinical effectiveness analysis, data for all patients recruited in the study were included. Inferential analyses included contingency analyses by hypothesis tests based on asymptotic chi- square distributions or by Fisher's exact tests when necessary, and Student's t-test analyses for continuous variables.

For the economic analysis, only the differences in direct health care costs between treatment arms were accounted for. In the cost calculation, the units of all relevant healthcare resources used in the patients' treatment were compared between the 2 treatment groups by hypothesis testing based on chi-square distributions for categorical variables or Student's t-test analyses for continuous variables. For those resources for which statistically significant differences between the groups were identified, the accounting cost was computed by multiplying the number of units used by its assigned unitary price (in 2002 euros) as referenced in the SOIKOS health economic evaluation database. Next, overall costs were estimated for each type of resource analyzed (disposable supplies, concomitant therapies, study drug acquisition costs, other antibiotics). Differences among types of resources were assessed by hypothesis testing based on Student's f-test analyses.

The primary endpoint was the cost per episode of febrile neutropenia treated, which added up to the different resource consumption items for which statistically significant differences had been first identified. Those items for which the differences in use between both treatment arms did not reach statistical significance (for example, the cost of gloves or that of needed transfusions), were not included in the calculation of the overall costs associated with the 2 therapeutic strategies.

For the safety analysis, all recruited patients' data were included: all eligible patients enrolled in the study were considered evaluable for this analysis, i.e. 190 patients in the I/ C arm and 183 patients in the P/T+A arm. Inferential analyses included contingency analyses by hypothesis tests based on asymptotic chi-square distributions.

For categorical variables, values are expressed as a percentage of the group from which they were derived. For continuous variables, values are expressed as the mean, and the standard deviation (SD). All p values were two-tailed, and p ≤ 0.05 indicated statistical significance. Two-sided 95% confidence intervals (95% CI) were calculated for the differences in response rates and overall accounting costs between both treatment groups.

Results

Characteristics of the study population

From March 1999 to June 2001, a total of 361 neutropenic patients with persistent fever were enrolled in the study (194 in the I/C group, 167 in the P/T + A group, which overall represent 92% of the planned enrolment), of whom 18 patients (5%) were not eligible for the following reasons: error in definition of treatment regimen (17 patients), and administration of parenteral antibiotics other than study regimens (1 patient). In addition, 53 eligible patients, 31 in the I/C group and 22 in the P/T+A group, were lost to followup and were not assessable for effectiveness. Thus, 290 patients (85% of the eligible cases) were evaluable in the primary analysis for response to empirical antibiotic therapy at Visit 4, 7 days after the start of antibiotic therapy, including 149 (51%) in the I/C group and 141 (49%) in the P/T+A group.

Due to the observational nature of this study and the high proportion of referral patients enrolled in the study, follow-up information beyond 7 days of study inclusion was not available in 48% of all valuable patients. Interestingly, there were no statistically significant differences in any baseline characteristics between pa\tients lost to follow-up in both treatment groups (31 in the I/C group and 22 in the P/T+A group). This fact makes unfeasible any effectiveness analyses beyond Visit 4 (7 days after therapy start), for which recurrence of fever on Day 14 after therapy initiation has not been considered in the effectiveness assessments.

At study inclusion, there were no significant differences between the 2 treatment groups in any characteristics of the 343 eligible patients (180 in the I/C group, 163 in the P/T + A group), including gender, age, weight, vital signs, duration and intensity of neutropenia, underlying disease, stem cell transplant, use of growth factors, previous oral antibiotic prophylaxis, presence and severity of mucositis, and other concomitant medical conditions (Table 1). In particular, the groups were well balanced with respect to stratification by category of underlying disease, with > 75% of the patients presenting with acute leukemia or lymphoma and > 30% having undergone a stem cell transplant. At study inclusion, the median number of days with neutrophil counts < 100 cells/l was 4 days, with no statistically significant differences between both treatment groups. Overall, no differences were found either in any of the laboratory parameters scrutinized, including blood hematology, chemistry, and coagulation.

A total of 187 episodes (55%) were classified as unexplained fever, with no statistically significant differences between the 2 treatment groups: 101 (56%) I/C, 86 (53%) P/T+A. For the remaining patients, the most frequent clinically documented infections were oropharyngeal infections (16%), gastro-intestinal infections (11%), lower respiratory tract infections (9%), and vascular device infections (8%), with no statistically significant differences between the 2 treatment groups. There were no significant differences between treatment groups in the occurrence of microbiologically documented infections: 38 febrile episodes (11%) were proven bacterial infections, the number being slightly higher in the P/T+A arm (14 [8%] for I/C, 24 [15%] for P/T + A; p = 0.04). Of those, the majority were bloodstream infections caused by Gram- positive pathogens.

Response rates

The response rates were compared for the 290 evaluable patients on Day 7 after therapy start (Table 2). A successful outcome was reported for 62 (42%) of 149 patients in the I/C group compared with 44 (31%) in the P/T+A group (p = 0.06; 95% CI for the difference between both response rates, -0.01 to 21.4%). On Visit 2 (72 hours after study inclusion), 76% of the patients in both treatment groups had experienced fever resolution. The distribution of the time to defervescence was estimated for each treatment group; a trend to a shorter time to defervescence was found in the I/C group (5.4 days for I/C, 5.9 days for P/T+A; p = 0.09). The distribution of the reasons for failure was not statistically different between the treatment groups. Similarly, there appeared to be no differences in effectiveness for the different types of clinically documented infections, including unexplained fever. For microbiologically documented infections, the successful eradication rates were 14% (2 of 14 patients) for I/C and 25% (6 of 24 patients) for P/T+A, the difference not being statistically significant (p = 0.68). The low numbers of patients with microbiologically documented infections in both treatment groups precluded further stratification of the effectiveness analysis. Relapse rates of favorable responders within 14 days of study inclusion were similar for both treatment groups: 5% for I/C and 11% for P/T+A (p = 0.51).

Table 1. Characteristics of the 343 eligible patients enrolled in the study

Table 2. Responses of patients to study therapy

Antibiotic regimen modification was frequently required; within 7 days of onset of study therapy, 90 (60%) of 149 patients in the I/C group and 84 (60%) of 141 patients in the P/T+A group required antibiotic regimen modifications. The most frequent modification of antibacterial study drug therapy consisted of the addition of a glycopeptide, vancomycin or teicoplanin (46% in the I/C group, 48% in the P/T + A group). The prescribed beta-lactam was replaced in 3% of the patients initially treated with I/C, and in 4% of those given P/T + A. I/C was supplemented with an aminoglycoside (either amikacin or tobramycin) in 7% of the cases. Additionally, ciprofloxacin was added to 4% of the patients treated with I/C, while amikacin was replaced with ciprofloxacin in 7% of the patients in the P/T+A group. The addition of antifungal therapy did not differ between the I/C group (fluconazole 9 patients, itraconazole 2, amphotericin B 13) and the P/T+A group (fluconazole 17 patients, itraconazole 1, amphotericin B 16). Finally, 19% of the patients received acyclovir.

Due to the observational nature of this study and the high proportion of patients referred from other health care centers enrolled in the study, follow-up information beyond 7 days of study inclusion was not available in 48% of the evaluable patients. This precluded any sound analysis of the occurrence of breakthrough infections in the study subjects.

Mortality

Within the complete follow-up period established in the protocol (14 days) and considering all available data, 10 (6%) of the 180 eligible patients enrolled in the I/C group and in 13 (8%) of the 163 eligible patients included in the P/T + A group, died. There were no statistically significant differences in overall mortality rates between treatment groups (p = 0.37). Mortality due to the presenting infection or further infection was relatively uncommon, most deaths being attributed to progression of the underlying disease, fatal hemorrhage, and other causes. No death was attributed to toxicity related to study antibiotic therapies.

Safety

All 343 eligible patients enrolled in the study were evaluable for adverse experiences on Day 7 after therapy initiation. Overall, the proportion of patients who developed adverse experiences was similar in the 2 treatment groups: 43 (24%) of 180 for I/C, 29 (18%) of 163 for P/T+A (p = 0.17). However, only 23 (13%) patients in the I/C arm and 9 (6%) in the P/T+A arm experienced an adverse reaction (regardless of intensity), i.e. an adverse experience considered possibly, probably or definitely related to the study drug (p = 0.03). When only moderate and severe adverse reactions were considered, no statistically significant differences were found between the 2 treatment groups (p = 0.09).

Nephrotoxicity deemed to be probably or definitely related to study therapy developed in 1 patient in the I/C group and in 3 patients in the P/T+A group. Hypokalemia related to the antibiotic regimen was reported for 3 patients in the I/C arm and for none in the P/T + A arm. Gastrointestinal intolerance, mainly nausea and vomiting, was reported for 10 patients (of mild intensity in 7 cases) in the I/C arm and for 1 patient in the P/T+A arm. Mild to moderate skin rashes occurred in 4 patients in each treatment arm.

The proportion of patients who required symptomatic treatment for an adverse reaction was similar in the 2 treatment groups: 6% for I/ C and 3% for P/T+A (p = 0.10). The study antibiotic regimen only had to be discontinued because of toxicity in 6 (3%) patients in the I/ C group and in 3 (2%) patients in the P/T+A group (p = 0.60).

Economic analysis

Considering the comparable effectiveness of both alternatives found in this study, a cost-minimization analysis was used to assess their relative efficiency. Table 3 displays the comparison between both treatment groups with respect to the amount of each resource element used during the study period considered (7 days after therapy start, the timeframe available for effectiveness assessments). There were only statistically significant differences between the 2 patient groups in the number of determinations of antibiotic plasma levels (p < 0.001) and pharmacokinetic studies performed (p = 0.002), and the number of antibiotic vials (p = 0.04) and of normal saline fluid bags (p = 0.045) used. Quantities were similar for both treatment groups for the remaining resource elements measured.

The proportion of patients who received additional concomitant therapies was comparable between the 2 treatment groups (98.7% for the I/C group, 97.9% for the P/T+A). No differences were detected in the type of concomitant therapies administered to the study subjects, with the only exception of erythropoietin, which was more frequent among patients treated with P/T+A. On the contrary, a higher proportion of patients treated with I/C received concomitant tobramycin (7% vs. 0%; p = 0.001).

For those items where statistically significant differences were identified, the accounting cost was computed by multiplying the quantity of each resource element used by its assigned unit price as referenced in the SOIKOS health economic evaluation database (Table 4). Accountable costs were consistently higher in the P/T + A group (non-pharmacological resources, p = 0.002; disposable material: p = 0.049; costs associated with the use of concomitant therapies, p = 0.049; drug acquisition costs (p < 0.001), with the only exception of costs associated with the concomitant use of other antibiotics, which was higher with I/C (p < 0.001). When overall accounting costs were compared between both treatment groups, P/T+A was 189.55 euros more costly than I/C (95% CI, 127.64 to 251.46 euros) per episode of febrile neutropenia. Most of this difference appeared to be attributable to the lower acquisition cost of I/C compared to P/ T+A, 170.72 euros lower per treatment course.

Table 3. Use of resource elements per episode of febrile neutropenia (evaluation on Day 7 post-onset of antibiotic therapy)

Discussion

The results of this study suggest similar effectiveness and lower costs of I/C compared with P/T+A in the initial empirical management of febrile \neutropenic patients. There was no significant difference in clinical effectiveness between the 2 treatment groups (I/C: 42%; P/T+A: 31%; difference: +10.4%; 95% CI: -0.01% to 21.4%; p = 0.06). Not surprisingly, the addition of an aminoglycoside to piperacillin/tazobactam did not seem to improve outcome. A recent meta-analysis of 29 randomized clinical trials pooling data from 4795 febrile episodes was set out to compare the efficacy of antibiotic monotherapy with that of combinations including an aminoglycoside for empirical treatment of febrile neutropenia10. The results of this analysis evidenced that monotherapy can be considered as effective as aminoglycoside-containing combinations. Interestingly, in our study the observed response rates of both treatment arms were lower than expected; the reported response rates from open and randomized trials range from 68% to 82%14 21. Similar favorable response rates have been reported for P/T+A9,29-31. The lower clinical response rates in our study may be explained to some extent by the high fraction of patients with acute leukemia or lymphomas (> 75%) or having undergone a stem cell transplant (> 30%). Yet, they most likely represent how efficacy compares to effectiveness in general; while efficacy measures the drug performance in an ideal setting and under strict protocol procedures that determine how the drug should be used and monitored ('what is the best outcome the drug is likely to produce'), effectiveness quantifies benefits expected from a therapeutic strategy and in a real setting ('what is the outcome the drug is likely to produce every day'). Because of the small number of patients in each treatment group with microbiologically documented infections, it was difficult to interpret the existence of differences in responses among the different clinical sites of infection and different infective organisms.

Table 4. Overall costs of study therapy per episode of febrile neutropenia (evaluation on Day 7 post-onset of antibiotic therapy)

The overall incidence of adverse effects with the 2 study treatment regimens was low. Several factors may have contributed to the low overall rate of adverse effects: the low dose of I/C (500 mg every 6 h i.v.) used, the twice daily dosing of amikacin, the exclusion from the study of patients with a prior history of severe renal failure or a Karnofsky score of < 30, and the protocol's emphasis on careful dose adjustments in those patients with impaired renal function. Nausea and vomiting were more frequently reported in the I/C group (7% vs. 1%; p = 0.02). Yet, in many cases this toxicity was mild or moderate and did not require symptomatic treatment. Seizures were not seen in our study. Rashes were evenly distributed between the 2 study arms. Nephrotoxicity deemed to be probably or definitely related to study therapy was reported in 1 patient treated with I/C and in 3 who received P/T+A; all 4 episodes were graded as mild or moderate. This adverse effect could be minimized with the early discontinuation of the aminoglycoside in those patients without microbiological documented infections. Overall, the safety results of this study favor the use of low doses of I/C (500 mg every 6h), which are otherwise probably as effective and definitely better tolerated than higher doses23.

To assess accurately the economic impact of the drug regimen selected in actual clinical practice, the analysis reported in this manuscript was based on the cost of a treatment course for all recruited patients. However, because of the heterogeneity of interventions and outcomes, and the differing severity of underlying diseases and infections, a full calculation of total cost from the perspective of the hospital was not feasible, and the economic evaluation concentrated on differences in the daily management costs, the cost of antibacterials, and the costs of managing adverse events related to them experienced in both study treatment arms. Although the 2 regimens were equivalent in terms of clinical effectiveness, the data suggest that compared with P/T+A, I/C is an efficient alternative that results in substantial savings in costs per patient treated. From the perspective of the Spanish National Health Insurance funds, I/C proved to be more cost-effective than P/ T+A in the treatment of fever associated with neutropenia. This result was driven by the lower acquisition costs of I/C (170.72 euros less costly than P/T+A per treatment course), and differences in other resources use. Several other studies have reported an advantageous costbenefit relation of initial therapy with imipenem versus other beta-lactam-based regimens32,33.

One of the main limitations of this observational study was the lack of effective follow-up data beyond 7 days after the start of antibiotic therapy. Other factors limiting the validity of the analysis herein reported could be the large heterogeneity of real- life patient populations, the lack of standardized indications for treatment, and the absence of rigorous experimental methodology. Nevertheless, the lack of differences between the patients lost in both groups, together with the fact that both therapeutic regimens were equally effective 7 days after therapy onset, may suggest that the study results may well reflect the reality of the total course of treatment for the patients. Thus despite its limitations, a study such as this provides useful information on the comparison of therapeutic alternatives in a current practice setting under standard conditions, and valuable guidance for clinicians in their daily decision-making.

Conclusion

In conclusion, the I/C regimen was as effective as the P/T+A regimen, with a consistent trend toward a better outcome associated with I/C compared with P/T+A. The I/C regimen was associated with a higher proportion of drug-related adverse experiences, and with a lower total treatment cost when compared with the P/T+A regimen. Further investigation is warranted in order to confirm the findings of this particular study.

Acknowledgements

This observational study was sponsored by Merck Sharp & Dohme of Spain. G.N. and C.S.-R. are employees of Merck Sharp & Dohme of Spain and potentially own stock and/or hold stock options in the company. The remaining authors have no conflict of interest with respect to the company sponsoring the study. The data entry and statistical analysis were performed by an independent company, Health Outcomes Research Europe, located in Barcelona, Spain.

* The results herein were presented in part at the XLIV Annual Meeting of the Spanish Society for Hematology and Hemotherapy (AEHH), Tarragona, Spain, 17-19 October, 2002.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2881_4, Accepted for publication: 17 March 2005

Published Online: 31 March 2005

doi:10.1185/030079905X43631

Miguel A. Sanz(a), Arancha Bermdez(b), Montserrat Rovira(c), Juan Besalduch(d), Maria-Jesus Pascual(e), Gonzalo Nocea(f) and Csar Sanz- Rodrguez(g) for the COSTINE Study Group(h)

a Servicio de Hematologe, Hospital Universitario La Fe, Valencia, Spain

b Servicio de Hematologa, Hospital Universitario Marqus de Valdecilla, Santander, Spain

c Servicio de Hematologa, Hospital Clinic i Provincial, Barcelona, Spain

d Servicio de Hematologa, Hospital Son Dureta, Palma de Mallorca, Spain

e Servicio de Hematologa, Hospital Carlos Haya, Malaga, Spain

f Department of Outcomes Research, Merck Sharp & Dohme of Spain, Madrid, Spain

g Department of Clinical Research, Merck Sharp & Dohme of Spain, Madrid, Spain

h Members of the Study Group are listed as contributing investigators in the Acknowledgements section

Address for correspondence: Dr Cesar Sanz-Rodriguez, Department of Clinical Research, Merck Sharp & Dohme of Spain, Josefa Valcarcel 38, 28027 Madrid, Spain; Tel.: +34-91-321-0886; Fax: +34-91-321- 0616; email: cesar_sanzrodriguez@merck.com

Centers participating in the COSTINE Study Group

Hospital Universitario La Fe, Valencia (Dr. Miguel A. Sanz); Hospital Universitario Marqus de Valdecilla, Santander (Dr. Julio Baro); Hospital Clnic i Provincial, Barcelona (Dr. Montserrat Rovira); Hospital Son Dureta, Palma de Mallorca (Dr. Juan Besalduch); Hospital Carlos Haya, Mlaga (Dr. Carlos Canal); Fundacin Jimnez Daz, Madrid (Dr. Jos F. Tomas); Hospital de Cruces, Barakaldo (Drs. Cristina Cortes and MariaJose Ojinaga); Hospital General Universitario Gregorio Maraon, Madrid (Dr. Tomas Pintado); Hospital Clnico Universitario, Salamanca (Dr. Jesus San Miguel); Hospital General, Albacete (Dr. J. Carlos Gomez); Hospital Virgen de la Victoria, Mlaga (Drs. Arturo Garriguez and Gemma Ramirez); Hospital Infanta Cristina, Badajoz (Drs. Roberto Bajo and Inmaculada Fuentes); Hospital Universitario La Laguna, Tenerife (Dr. Manuel Hernandez).

Copyright Librapharm May 2005

Source: Current Medical Research and Opinion

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