Levofloxacin in the empirical treatment of patients with suspected bacteraemia/sepsis: comparison with imipenem/cilastatin in an open, randomized trial

A. Geddesa,*, M. Thalerb, S. Schonwaldc, M. Härkönend, F. Jacobse and I. Nowotnyf

a Department of Infectious Diseases, University of Birmingham Medical School, Edgbaston, Birmingham, UK b Infectious Diseases Unit, Chaim Sheba Medical Centre, Tel-Hashomer, Israel. c University Hospital of Infectious Diseases, Zagreb, Croatia. d Porvoo District Hospital, Porvoo, Finland. e Erasme Hospital, Infectious Diseases Clinic, Brussels, Belgium. f Hoechst Marion Roussel, Frankfurt, Germany


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
An open, randomized, multinational, multicentre study was conducted to compare the efficacy, safety and tolerability of levofloxacin 500 mg twice daily with imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized adult patients with clinically suspected bacteraemia/ sepsis. Levofloxacin patients could change from iv to oral administration after a minimum of 48 h iv treatment if clinical signs and symptoms of sepsis had improved. The primary efficacy analysis was based on the clinical and bacteriological response at clinical endpoint. A total of 503 patients were randomized and 499 included in the intent-to-treat population. The per-protocol population comprised 287 patients with bacteriologically proven infection. Clinical cure rates at clinical endpoint in the intent-to-treat population and per-protocol population were 77% (184/239) and 89% (125/140), respectively, for levofloxacin and 68% (178/260) and 85% (125/147), respectively, for imipenem/cilastatin. At follow-up, the cure rates in the per-protocol population were 84% for levofloxacin and 69% for imipenem/cilastatin. The 95% confidence interval for both populations showed that levofloxacin was as effective as imipenem/cilastatin. A satisfactory bacteriological response was obtained in 87% (96/110) of levofloxacin patients and 84% (97/116) of imipenem/cilastatin patients at clinical endpoint. Adverse events possibly related to the study drug were reported in 74 (31%) levofloxacin patients and 79 (30%) imipenem/cilastatin patients. There were no clinically appreciable differences between the treatment groups. Levofloxacin 500 mg twice daily, either iv or as sequential iv/oral therapy, was as effective and well tolerated as imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized patients with suspected bacteraemia/sepsis.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Bacteraemia is a major cause of morbidity and mortality, occurring in c. 250,000 hospitalized patients per year in the USA, and increasing the risk of death by up to 20-fold.1,2,3 The incidence of bacteraemia is increasing, with Gram-positive pathogens being predominant, although Gram-negative bacteraemia is associated with higher mortality rates. Commonly isolated Gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter aerogenes and Enterobacter cloacae.4,5 Staphylococcus epidermidis has become a major causative pathogen and Staphylococcus aureus and Enterococcus spp. have also become increasingly prevalent.1,2,3,45 Of concern is the occurrence of increasingly virulent strains that are resistant to multiple antibiotics such as methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE), as well as vancomycin-resistant Enterococcus faecalisand Enterococcus faecium (VRE).

Sepsis is defined as the systemic response to severe infection in a critically ill patient. A new set of terms and definitions to describe accurately each stage of the inflammatory response was introduced in 1991 by the American College of Chest Physicians/Society of Critical Care Medicine.6 Sepsis, sepsis syndrome and septic shock are the increasingly severe stages of the same disease process. If not diagnosed and treated promptly, sepsis may become self-perpetuating and the elderly are particularly at risk of high mortality.7 The clinical manifestations of sepsis are identical for both Gram-negative and Gram-positive pathogens. According to Bone,8 a diagnosis of sepsis should be considered when two or more of the following symptoms are present: temperature >38°C or <36°C; heart rate > 90 beats/min; respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg; white blood cells >12,000/µL or <4000/µL or >10% band forms.

Because of the high risk of mortality and morbidity associated with bacteraemia/sepsis, treatment is necessarily empirical and a broad-spectrum antimicrobial agent is required. The major pathogens in different institutions or geographical areas may vary widely owing to local factors such as the patient population and the pattern of antibiotic use.9 The likely causative pathogen(s) should be considered before empirical treatment is initiated.

Levofloxacin, a fluoroquinolone antibiotic, is the L-isomer of the racemate ofloxacin. It is approximately twice as active as the equivalent amount of ofloxacin in vitro since the antibacterial activity of ofloxacin is associated almost totally with the L-isomer.10,11 It has a broad spectrum of activity including Gram-positive aerobes, Gram-negative aerobes, atypical bacteria and anaerobes.10,11,12,13,14,15,16,17,18,19,20 Levofloxacin is rapidly absorbed with 100% oral bioavailability and good tissue penetration.21,22 Efficacy has been demonstrated in a number of infections including pneumonia, acute exacerbation of chronic bronchitis, urinary tract infections and skin and soft tissue infections (SSTI).23,24,25,26 Levofloxacin is currently thought to be a useful agent for the treatment of bacteraemia/sepsis.

The purpose of this study was to investigate the efficacy and tolerability of levofloxacin in the treatment of bacteraemia/sepsis compared with that of imipenem/cilastatin. Imipenem is a carbapenem with a broad spectrum of activity including ß-lactamase-producing species. It is co-administered with cilastatin, a renal dehydropeptidase inhibitor that prevents the renal metabolism of imipenem. Imipenem/cilastatin has been widely used in the treatment of severe infections including bacteraemia/sepsis.27,30 The hypothesis tested was that levofloxacin was as effective and well tolerated as imipenem/cilastatin in the treatment of bacteraemia/sepsis.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design

This was a multinational, open, centrally randomized, stratified, comparative study of levofloxacin 500 mg bd, either iv or iv/oral switch therapy, and imipenem/cilastatin 1 g iv tid. Patients were randomized to receive levofloxacin or imipenem/cilastatin. Randomization was 1:1 and was performed using a central computerized procedure. A sequence of patient numbers was assigned to each study centre and patients were numbered consecutively, in the order in which they entered the study. The study drug was randomly assigned to, and labelled with, the patient numbers in advance of the study. Levofloxacin and imipenem/cilastatin were randomized 1:1, stratified according to a ‘Simplified Sepsis Score' (SSS) (high-risk group>>=31, low-risk group><=30) and to the need for initial antibiotic monotherapy or combination treatment. Randomization was balanced within each stratum at each centre. The SSS was based on the sum of points assigned to six physiological variables plus points assigned according to the patient's age. For each variable, the most unfavourable value, i.e. the one furthest from the predefined midpoint given in the study protocol, was selected from all the values measured in the 24 h before study entry. The variables were: heart rate, blood pressure, temperature, respiratory rate, modified Glasgow Coma Score31 and white blood cell count. All values had to be available for randomization to be performed and the score points were assigned by the central computer. The stratification procedure is shown in Figure 1.



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Figure 1. Stratification procedure for patient randomization. *Patients with clinically suspected or proven intra-abdominal infection or gynaecological infection were assigned to this group, regardless of whether they received initial combination therapy (in the levofloxacin group) or initial monotherapy (in the imipenem/cilastatin group). Combi, combination therapy; IPM/CS, imipenem/cilastatin; LVFX, levofloxacin; Mono, monotherapy; SSS, Simplified Sepsis Score.

 
Patients in the levofloxacin group could be changed from iv to oral treatment after a minimum of 48 h iv treatment if clinical signs and symptoms of sepsis had improved. The duration of treatment was at the discretion of the investigator and was based on the clinical response. Treatment was recommended to be continued for 2 days after fever subsided. A minimum duration of 48 h treatment was required for a patient to be evaluable unless the pathogen responsible was resistant to the assigned antibiotic. Patients were given a second antimicrobial agent in combination with the assigned study drug as follows: (i) patients with clinically suspected or proven intra-abdominal infection and/or gynaecological infection were given metronidazole in addition to levofloxacin; (ii) patients with an infection strongly suspected to be caused by Pseudomonas spp. were given an aminoglycoside in addition to either study drug; (iii) patients with an infection strongly suspected to be caused by MRSA were given vancomycin in addition to the study drug.

The protocol was approved by the relevant local Ethics Committee and the study was conducted in accordance with the Good Clinical Practice Guidelines of the European Community and the Declaration of Helsinki.

Patients

Patients were enrolled into the study before the bacteriological results were available. Inclusion criteria were: adult patients >=18 years old) of either sex; clinical evidence of infection e.g. respiratory tract infection (RTI), urinary tract infection (UTI), intra-abdominal infection; a systemic response to infection manifested by two or more of the following conditions: body temperature >38°C or <36°C, heart rate > 90 beats/min, respiratory rate >20 breaths/min or PaCO2 < 32 mm Hg (4.3 kPa), leucocytes >12,000/mm3 or <4000/mm3 or >10% band forms; a condition requiring treatment with a broad-spectrum antibiotic such as levofloxacin or imipenem/cilastatin. Exclusion criteria included: known responsible pathogen at study entry; antibiotic treatment for more than 24 h in the 5 days before study entry; ofloxacin or imipenem/cilastatin treatment for this infectious episode; any known or suspected bacterial infection; treatment with any study drug in the 4 weeks before study entry; hypersensitivity to fluoroquinolones or ß-lactams; pregnancy or breastfeeding; neutropenia <1000 neutrophils/mm3). At baseline, the patients were assessed for APACHE III score.32 Written informed consent was obtained from all patients.

Efficacy analysis

The primary efficacy variable was the clinical response based on infection-related signs and symptoms, including chest X-ray for patients with an entry diagnosis of pneumonia. Clinical and bacteriological assessments were performed at clinical endpoint (1–5 days after the last day of treatment) but only a clinical assessment was performed at follow-up (10–30 days after the last day of treatment). The primary efficacy variable was the cure rate at clinical endpoint. Assessments were performed by computer (referred to as the protocol assessment) and by the investigator. Summary data for selected patients were assessed by an independent evaluator. These patients included all those in the intent-to-treat population who had different outcomes in the protocol and investigator assessments, and randomly selected patients who were classed as cured in both of these assessments. Analyses were performed on the clinical response in the intent-to-treat population (all patients who received at least one dose) and the per-protocol population (all treated patients with clinical signs and symptoms of sepsis and bacteriologically proven infection, excluding major protocol violators). Major protocol violators, who were not included in the per-protocol population, were patients with incorrect entry diagnosis, incorrect treatment duration, systemic antibiotic pretreatment or a missing or out of time-window post-treatment clinical evaluation.

Subgroup analyses of the clinical cure rates were planned in the following patient groups: patients with Streptococcus pneumoniae in baseline cultures; patients with E. coli in baseline culture; patients with entry diagnosis pneumonia/RTI; patients with entry diagnosis pyelonephritis/UTI; patients with entry diagnosis intra-abdominal infection. However, the patient numbers in each of these groups were too low for a meaningful analysis.

Clinical

The clinical response was evaluated at clinical endpoint according to the following definitions. (i) Cure: all infection-related signs and symptoms had disappeared or returned to preinfection state; at least one infection-related sign or symptom had improved, the patient was afebrile and no subsequent antibiotic therapy had been started for the treatment of the disease under investigation. (ii) Failure: all infection-related signs and symptoms remained unchanged or worsened; the patient developed new clinical findings consistent with active infection requiring new antibiotic treatment; the patient died owing to the infectious episode for which they were enrolled; the study drug was discontinued because of clinical and/or bacteriological treatment failure; one or more antibiotics were added to the study drug because of treatment failure; at least one infection-related symptom had improved but a subsequent antibiotic treatment was started for the disease under investigation. (iii) Indeterminate: circumstances precluded classification as cure or failure (e.g. missing follow-up information, discontinuation of treatment because of non-efficacy-related reasons, major protocol violations, death not due to infectious disease).

At follow-up, the assessment of clinical response was based on signs and symptoms of infection and change to another antibiotic. The definitions were: (i) cure: no appearance of infection; (ii) failure: clinical response was failure at clinical endpoint, subsequent antibiotic treatment owing to clinical or bacteriological failure, or clinical signs or symptoms of a new infection; (iii) indeterminate: no follow-up assessment available or clinical response was indeterminate at clinical endpoint.

Bacteriological

Appropriate cultures were obtained for the isolation, identification and susceptibility testing of the causative pathogen(s) in the 48 h before the start of therapy, on day 2 or 3 of treatment and at each efficacy evaluation (clinical endpoint, follow-up (optional), before modification of treatment except when due to an adverse event, and before the switch from iv to oral levofloxacin). At least two sets of blood cultures (aerobic and anaerobic) were set up for all patients before the start of therapy. In patients with persistent fever, blood cultures were repeated after 48 h treatment. Patients were eligible for evaluation of bacteriological response if a pathogen was isolated in a baseline culture and there were no major protocol violations. The bacteriological response was defined from the clinical endpoint culture as (i) satisfactory [baseline pathogen was eradicated (eradication); the patient had improved clinically so that a follow-up culture could not be obtained (presumed eradication); a new pathogen was present at any site without clinical evidence of infection (colonization)]; (ii) unsatisfactory, i.e. bacteriological failure [baseline pathogen was still present (persistence); a new pathogen emerged at any site during treatment or within 3 days after treatment (superinfection); eradication of baseline pathogen was followed by replacement with a new pathogen at the same site more than 3 days after completion of treatment (eradication and reinfection); persistence of baseline pathogen was accompanied by a new pathogen at the same site (persistence and reinfection); new or additional antibiotic treatment was given owing to clinical evidence of continued infection (presumed persistence); new or additional antibiotic treatment was given because the baseline pathogen was resistant to the study drug (resistance)]; or (iii) indeterminate (lack of opportunity to obtain subsequent cultures; treatment of the patient with a systemic antibiotic in addition to the study drug).

Safety

All patients who received at least one dose of study drug were evaluated for safety. Adverse events were reported spontaneously by patients or were observed by the investigator and their intensity (mild, moderate or severe) and possible relationship to the study drug were assessed by the investigator. Adverse events were classified as serious or non-serious. Patients were withdrawn from the study immediately in the case of a serious adverse event that was possibly related to the study drug. A serious adverse event was defined as: fatal or life threatening; permanently or significantly disabling; required or prolonged hospitalization; involved cancer or congenital anomaly; occurred as a result of overdose; suggested a significant hazard.

Statistical analyses

The primary efficacy variable was the cure rate 1–5 days after the end of treatment (clinical endpoint). Assuming a success rate of 80% in both treatment arms and a {delta} of 15% (maximum difference between treatments to be accepted as equivalent), 112 evaluable patients per group were needed to provide an 80% chance of showing equivalence (power = 80%).33,34 It was assumed that 50% of the patients treated would be evaluable for efficacy, therefore, 450 patients were to be enrolled.

The primary efficacy analysis focused on the clinical cure rate in the per-protocol population determined 1–5 days after the end of treatment (protocol assessment). A two-sided 95% confidence interval (CI) was calculated for the difference in cure rates. If the upper bound was >0 and the lower bound >–0.15, levofloxacin was considered to be as effective as imipenem/cilastatin.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 503 patients with clinically suspected sepsis were enrolled and randomized at 47 centres in 13 countries between September 1995 and December 1996. Figure 2 shows the number of patients at each phase of the study. Four patients were randomized but did not receive study medication, giving an intent-to-treat population of 499 patients. Demographic characteristics were similar in both treatment groups (see Table I). The mean age was 59 years (range 18–92) and 49% were >=65 years old. The majority of patients (90%) were white and approximately half (57%) were male. Histories of disease and/or concomitant illnesses were reported in 94% (468) of patients. The most commonly reported underlying diseases were renal/genitourinary (36%, 179), respiratory (33%, 166) and cardiovascular (32%, 160). Diabetes mellitus was reported in 68 patients (14%) and drug/alcohol abuse in 80 patients (16%). Fifty-five patients (11%) had neuropsychiatric diseases and 299 (60%) had undergone surgical procedures.



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Figure 2. Number of patients at each phase of the study.

 

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Table I. Patient characteristics (intent-to-treat population)
 
Characteristics of the basic illness were similar for both treatment groups (see Table II). Pneumonia/RTI was the most common source of sepsis (47%, n = 232), either alone or in combination with other infections. Of the infections, 94% (n = 219) were confirmed by X-ray findings. The next most common infections were pyelonephritis/UTI (28%, n = 139) and intra-abdominal infection (10%, n = 52). The majority of all patients had community-acquired infections (82%, n = 409). There were no major differences between the treatment groups for SSS or APACHE III. The median SSS was 22 (range 0–63), with 107 patients (21%) having a SSS of at least 31. The median APACHE III score was 46 (range 6–106). Pretreatment with systemic antibiotics for less than 24 h in the 5 days before study entry was reported in 180 patients (36%). The most commonly prescribed antibiotics were cephalosporins, penicillins and ß-lactamase inhibitors. Only 19 patients (4%) received no concomitant medication.


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Table II. Diagnosis at study entry
 
A total of 104 patients (21%) did not complete the study and were withdrawn for various reasons (see Table III). Some patients had more than one reason for withdrawal. The number of patients withdrawn owing to non-efficacy/safety reasons was higher in the imipenem/cilastatin group. A total of 207 levofloxacin patients (87%) and 215 imipenem/cilastatin patients (83%) were assigned to initial monotherapy. A further 24 patients in the imipenem/cilastatin group, who were enrolled with suspected or proven intra-abdominal or gynaecological infections, also received imipenem/cilastatin monotherapy to provide activity against anaerobes. Thus, 239 imipenem/cilastatin patients (92%) were on initial monotherapy. The remaining patients received combination therapy, the majority with two agents.


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Table III. Reasons for premature withdrawal from study medication
 
The initial antibiotic regimen was maintained throughout the study in 199 levofloxacin (83%) and 205 imipenem/cilastatin patients (79%). At least one antibiotic was added to the initial regimen for efficacy-related reasons in 10 levofloxacin (4%) and eight imipenem/cilastatin (3%) patients. Treatment was changed to a different antibiotic regimen in 22 levofloxacin (9%) and 37 imipenem/cilastatin (14%) patients because of treatment failure, adverse events or other reasons. Of the patients who started on monotherapy, the initial antibiotic regimen remained unchanged in 174 levofloxacin (84%) and 194 imipenem/cilastatin (81%) patients. The median treatment duration, whether mono- or combination therapy, was 9 days for levofloxacin and 8 days for imipenem/cilastatin.

There were 31 (6%) patients with 36 major protocol violations, namely: incorrect treatment duration, no clinical endpoint evaluation/out of time-window, incorrect entry diagnosis and antibiotic pretreatment. The type and frequency of protocol violation were similar in both treatment groups. A baseline pathogen was not isolated in 160 (32%) patients giving a per-protocol population of 308 patients, 62% of the patients enrolled. Twenty-one patients whose clinical response was classified as indeterminate were excluded from the per-protocol analysis: four in the levofloxacin group and 17 in the imipenem/cilastatin group (see Table IV and Figure 2); 19 were withdrawn after the minimum treatment period of 2 days due to non-efficacy-related reasons. The remaining two patients died during treatment with study drug. These were not regarded as treatment failures as death was not thought to be due to the disease for which the study drug was given.


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Table IV. Clinical response at clinical endpoint (1–5 days after the end of treatment)
 
The clinical response in the intent-to-treat population is shown in Table IV. The cure rate for levofloxacin (77%) was higher than that for imipenem/cilastatin (68%). The 95% CI was 0.8;16.3, indicating that levofloxacin was as effective as imipenem/cilastatin. In the per-protocol population, the cure rate for levofloxacin was similar (89%) to that for imipenem/cilastatin (85%) (Table IV). The 95% CI was –3.5;12.0, indicating that levofloxacin was as effective as imipenem/cilastatin. The cure rates in both treatment groups were higher in the per-protocol population than in the intent-to-treat population due to the higher number of indeterminate cases in the latter, mainly due to protocol violations, which were classed as failures. Of the patients who were classed as failures in the per-protocol population, additional antibiotic treatment was started before the end of study treatment in 18 (levofloxacin, eight; imipenem/cilastatin, 10). In total, 12 of the 15 levofloxacin failures and 14 of the 22 imipenem/cilastatin failures received subsequent antibiotic treatment within 5 days after the end of study treatment owing to clinical and/or bacteriological failure.

Treatment with subsequent antibiotics within 5 days after the end of study treatment was necessary for 35 (15%) levofloxacin and 96 (37%) imipenem/cilastatin patients in the intent-to-treat population and for 14 (10%) and 45 (31%), respectively, in the per-protocol population. In both populations, more imipenem/cilastatin than levofloxacin patients were prescribed subsequent antibiotics for non-efficacy-related reasons. Antibiotics prescribed for efficacy-related reasons were mostly given for clinical failure with or without bacteriological failure and less frequently for bacteriological failure alone. Only five patients in each treatment group received subsequent antibiotic treatment owing to bacteriological failure. Two patients in the imipenem/cilastatin group received additional but not subsequent antibiotic treatment owing to bacteriological failure (Table III).

The clinical response at clinical endpoint according to the investigator was similar to the protocol assessment for each study drug in both the intent-to-treat and per-protocol populations, with cure rates of 80% and 86%, respectively, for levofloxacin and 74% and 80%, respectively, for imipenem/cilastatin. The protocol and investigator assessments of clinical response were in agreement for 318 of 375 patients (85%) who had both assessments in the intent-to-treat population and for 209 of 238 patients (88%) who had both assessments in the per-protocol population. A total of 155 patients was selected for assessment by an external evaluator. The protocol and independent evaluator assessments of clinical response were in agreement for 97 patients (63%) in the intent-to-treat population and 59 of 83 patients (71%) in the per-protocol population. The differences were random with approximately equal numbers of cases being reclassified as either cure or failure. At follow-up, the cure rates in the intent-to-treat and per-protocol populations for levofloxacin and imipenem/cilastatin were 81% and 84%, and 70% and 69%, respectively.

A change from iv to oral levofloxacin therapy was made in 176/239 (74%) patients. Of these, the majority (74%, 130) changed on days 2–5 of iv treatment. The median time of change was on day 4. One hundred and sixty-two of the 176 patients were cured.

The duration of hospitalization was analysed for 446 (89%) patients. The median time between start of treatment and hospital discharge for levofloxacin was 9 days for both the intent-to-treat and per-protocol populations compared with 11 and 11.5 days, respectively, for imipenem/cilastatin. This difference was statistically significant for both populations (P = 0.015).

The median treatment duration in the intent-to-treat population was 9 days for levofloxacin and 8 days for imipenem/cilastatin. For clinically cured patients who received purely iv therapy, either imipenem/cilastatin or levofloxacin, the mean treatment duration was 8 days compared with 10 days for those who received sequential levofloxacin.

A pathogen was isolated at baseline in 308 patients (62%), 144 (60%) in the levofloxacin group and 164 (63%) in the imipenem/cilastatin group. A total of 436 bacterial isolates were obtained at baseline. The most common pathogens >10 isolates in at least one treatment group) were E. coli and S. pneumoniae (Table V). The most common pathogens isolated from blood cultures were E. coli, S. pneumoniaeand K. pneumoniae. The distribution of pathogens between the treatment groups was similar. Of 365 aerobic isolates, eight (2%) were resistant to imipenem/cilastatin and 15 (4%) to levofloxacin. Of 162 tested aerobes isolated from patients assigned to levofloxacin, four (3%) were resistant to levofloxacin. In the imipenem/cilastatin group, eight of 203 isolates (4%) were resistant to the assigned study drug.


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Table V. Most common pathogens at baseline
 
The satisfactory bacteriological response rate, in the per-protocol population at clinical endpoint, was similar in both levofloxacin (96/110; 87%) and imipenem/cilastatin (97/116; 84%). A total of 82 patients had an indeterminate response giving a total of 226 patients who were included in the analyses. Persistent or presumed persistent pathogens were the main reason for an unsatisfactory response (levofloxacin, seven; imipenem/cilastatin, 14). The 95% CI was –5.5;12.8, indicating that levofloxacin was as effective as imipenem/cilastatin. The investigator assessment was higher than the protocol assessment for both treatment groups (94% and 88%, respectively). In the per-protocol population analysis, bacteriological and clinical response were in agreement for 206 of 220 patients (94%) who had evaluable data for both assessments. There were 10 patients who had an unsatisfactory bacteriological response but the clinical response was cure (levofloxacin, three; imipenem/cilastatin, seven). Three patients, all in the imipenem/cilastatin group, had a satisfactory bacteriological response but a failed clinical response. The remaining patients had an indeterminate bacteriological or clinical response. Eradication rates for the most common responsible pathogens, excluding those isolated from patients with an indeterminate response, are shown in Table VI. The eradication rates for levofloxacin and imipenem/cilastatin were similar.


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Table VI. Pathogen eradication rates
 
The sources of the baseline pathogen in patients who had an unsatisfactory bacteriological response were similar in both treatment groups and included blood, sputum, urine, skin/wound swab, transtracheal aspiration and bronchoalveolar lavage. The pathogens involved were also similar in both groups and included S. aureus, S. epidermidis, S. pneumoniae,K. pneumoniae, E. coliand P. aeruginosa.

All 499 patients in the intent-to-treat population were evaluable for safety. Haematological and clinical chemistry variables showed only minor changes from baseline to clinical endpoint except for a slight increase in platelets and bilirubin and a decrease in leucocytes and neutrophils. The changes were similar for both treatment groups. Laboratory abnormalities classed as adverse events were reported in 116 (23%) patients (levofloxacin: 25%, 60; imipenem/cilastatin: 22%, 56).

Adverse events, not necessarily drug related, were reported in 290 (58%) patients whilst adverse events assessed by the investigator as possibly related to the study drug were reported in 153 patients (31%) (Table VII). For all adverse events, the most commonly affected body systems >10% of patients in at least one treatment group) were similar in both groups: digestive system, metabolic and nutritional disorders, body as a whole, cardiovascular system, respiratory system, nervous system, and haemic and lymphatic system. The most common urogenital system event was urine abnormality (levofloxacin, no patients; imipenem/cilastatin, five patients). The most common digestive system events were nausea (levofloxacin, 12; imipenem/cilastatin, 22) and vomiting (levofloxacin, seven; imipenem/cilastatin, 10). The most common nervous system events were headache (levofloxacin, four; imipenem/cilastatin, nine), insomnia (levofloxacin, six; imipenem/cilastatin, six) and anxiety (levofloxacin, six; imipenem/cilastatin, four). In the levofloxacin group, five patients suffered from a myocardial infarction compared with no cases in the imipenem/ cilastatin group. However, the study investigators assessed that, in their clinical judgement based on the patients' medical history, none of these cases were related to study drug.


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Table VII. Adverse events
 
The spectrum of possibly drug-related adverse events was similar to that for all adverse events. There were no relevant differences between the treatment groups. Possibly related events of the cardiovascular system were relatively rare in both groups. The frequency of possibly related nervous system events was similar with both drugs, the most common being headache (levofloxacin, four; imipenem/cilastatin, nine). Tendon disorder, without rupture, was reported in one levofloxacin patient.

Study treatment was permanently discontinued owing to adverse events in 16 levofloxacin patients (7%) and 18 imipenem/cilastatin patients (7%). There were 35 deaths during the study (levofloxacin: 6%, 15; imipenem/cilastatin: 8%, 20) of which 17 occurred during treatment, 14 between the end of treatment and follow-up, and four occurred after the follow-up period. These were not regarded as treatment failures because none of the members of the Data Review Committee (Prof. Carbon, Paris, France; Prof. Geddes, Birmingham, UK; Prof. Norrby, Lund, Sweden; Prof. Shah, Frankfurt, Germany) assessed the death to be due to the disease for which the study drug was given. The adverse events associated with the deaths were largely due to severe pre-existing conditions and none were considered by the investigator to be causally related to the study drug. The mortality rate in the high-risk stratum, defined as an SSS of >=31 points, was significantly higher (21/107 patients, 20%) than the mortality rate for patients with a SSS <31 (10/392, 3%; P = < 0.001) irrespective of study drug. Initial combination therapy was not a risk factor for mortality. The APACHE III score had the highest predictive value for mortality (P = <= 0.0001) followed by the age of the patient (P = 0.058). There was no difference in mortality between the treatment groups.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The patient population in this study was well matched in both treatment groups in terms of baseline characteristics and baseline pathogens except for S. aureus where there were six isolates in the levofloxacin group and 22 in the imipenem/cilastatin group. The results indicate that levofloxacin is as effective as imipenem/cilastatin in the treatment of bacteraemia/sepsis. The clinical cure rates for the primary efficacy analysis in the per-protocol population were 89% for levofloxacin and 85% for imipenem/cilastatin and 77% and 68%, respectively, in the intent-to-treat population. The higher cure rates obtained in the per-protocol population were due to the larger number of indeterminate cases in the intent-to-treat population, due mainly to protocol violations, which were classed as failures. The cure rates according to the investigator assessments were similar to the protocol assessment for both populations and both treatment groups. The satisfactory bacteriological response rate was also similar in both treatment groups (87% and 84%, respectively).

The cure rate for levofloxacin obtained in this study is similar to that reported in trials with this agent in other infections. Clinical success rates have been reported of 93% in UTIs,23 95% in acute exacerbation of chronic bronchitis,24 96% in SSTI25 and 98% in community-acquired pneumonia.26 Likewise, the cure rates with imipenem/cilastatin (85%) are similar to the clinical success rates of 77–82% reported in studies of serious infections and bacteraemia/sepsis.27,28,29,30

The number of patients withdrawn from the study for non-efficacy-/safety-related reasons and the number of patients who were prescribed subsequent antibiotics for non-efficacy-related reasons were higher in the imipenem/cilastatin group. This may have been due to a tendency to switch imipenem/cilastatin patients to an oral antibiotic regimen in order to discharge them from hospital early. In some countries, especially in Israel, Norway, South Africa and Sweden, it is hospital policy to discharge patients as early as possible. In the levofloxacin group, patients were discharged as soon as they were switched from iv to oral therapy. In the imipenem/cilastatin group, patients should have remained in hospital for the whole treatment period according to the protocol, since imipenem/cilastatin was administered intravenously. Patients may have been withdrawn from the study for reasons given as administrative, patient request or non-compliance when the investigator wanted to discharge an imipenem/cilastatin patient.

The median treatment duration in the intent-to-treat population was similar for both drugs (9 days for levofloxacin and 8 days for imipenem/cilastatin). The mean treatment duration for clinically cured patients who received only iv therapy, either imipenem/cilastatin or levofloxacin, was shorter (8 days) than that for patients who received sequential levofloxacin (10 days). The median time from start of treatment to hospital discharge was longer for imipenem/cilastatin patients (11 days in the intent-to-treat and 11.5 days in the per-protocol populations) than for levofloxacin patients (9 days in both populations). This difference was statistically significant for both populations (P = 0.015).

There were few clinically noteworthy abnormal laboratory values and these were similar in both treatment groups. The incidence of all and possibly drug-related adverse events, and the body systems affected, were similar in both treatment groups, although there was a slight difference for all events for body as a whole, urogenital and digestive systems. However, the small number of tests performed must be borne in mind when considering this difference.

In conclusion, the results of this study show that sequential iv/oral treatment with levofloxacin is as effective as iv imipenem/cilastatin in the treatment of hospitalized patients with suspected bacteraemia/sepsis.


    Acknowledgments
 
The authors would like to thank the following investigators for their participation in this study: Austria: W. Ilias; Belgium: L. Huyghens, E. Installé, J. Nagler, P. Paris, G. Siska, J. P. Thys, B. Vandercam; Denmark: A. Engquist; Finland: K. Sammalkorpi, M. Valtonen; Germany: H. Koch; Israel: R. Finkelstein, E. Rubinstein, F. Schlaeffer, M. Shapiro, Y. Siegman-Igra; Italy: M. Sarpellon, S. Vesconi; Netherlands: I. M. Hoepelman, M. Kunst, S. Lobatto, M. van Westreenen; Norway: O. Brubakk, B. von der Lippe, R. Reiersen, H. Sjursen; South Africa: J. Killian, U. G. Lalloo, D. Linton, G. E. Naude, W. van Vuuren; Spain: J. Carratalà, F. Garcia Bragado, M. Gurgui Ferrer, C. Leon, M. Sabria; Sweden: L. Burman, C. Hansson, B. Hill, B. E. Malmvall, I. Odenholt, A. Runehagen, C. Söderström, I. Vig. This study was supported by Hoechst Marion Roussel.


    Notes
 
* Corresponding author. Tel: +44-161-414-6956; E-mail: geddesan{at}birmingham.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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Received 24 February 1999; returned 4 May 1999; revised 1 July 1999; accepted 2 August 1999