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
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Abstract |
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Introduction |
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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.
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Patients and methods |
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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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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 (15 days after the last day of treatment) but only a clinical assessment was performed at follow-up (1030 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 15 days after the end of treatment
(clinical
endpoint). Assuming a success rate of 80% in both treatment arms and a 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 15 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.
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Results |
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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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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 25 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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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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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.
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Discussion |
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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 7782% 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.
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Acknowledgments |
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Notes |
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References |
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Received 24 February 1999; returned 4 May 1999; revised 1 July 1999; accepted 2 August 1999