Comparative study of levofloxacin and amoxycillin/clavulanic acid in adults with mild-to-moderate community-acquired pneumonia
Corresponding author and reprint requests: Claude Carbon, CHU Bichat Claude Bernard, Service Medecine Interne, 46 rue Henri Huchard, 95877, Paris Cedex 18, France Tel: +33 1 4025 7000 Fax: +33 1 4025 8845 E-mail: email@example.com
Objective: To compare the efficacy and safety of two different doses of levofloxacin with amoxycillin/clavulanic acid in the treatment of community-acquired pneumonia.
Methods: A double-blind, randomized (1:1:1), double-dummy, three-arm parallel design, multicenter study was conducted in adult patients with mild-to-moderate community-acquired pneumonia. In total, 518 patients were randomized to receive levofloxacin 500 mg once daily, levofloxacin 500 mg twice daily or amoxycillin/clavulanic acid 625 mg three times daily for 7–10 days.
Results: The clinical cure rates post-therapy (2–5 days after the end of treatment) in the intent-to-treat population were 84.2% (144/171) in the levofloxacin once-daily group, 80.2% (142/177) in the levofloxacin twice-daily group and 85.7% (144/168) in the amoxycillin/clavulanic acid group. In the per-protocol population, the clinical cure rates post-therapy were 95.2% (138/145), 93.8% (137/146) and 95.3% (141/148), respectively. The total pathogen eradication rates were 97.8%, 100% and 97.5%, respectively. Both drugs were equally well tolerated and no major adverse events were observed.
Conclusions: Levofloxacin was effective, safe and well tolerated in the treatment of mild-to-moderate community-acquired pneumonia. A complementary analysis indicated that there was no difference in therapeutic outcome between levofloxacin 500 mg once daily and twice daily. Levofloxacin 500 mg once daily, for 7–10 days, is an effective and safe treatment for mild-to-moderate community-acquired pneumonia in adults.
Community-acquired pneumonia (CAP) is an acute lower respiratory tract illness which is usually associated with fever, focal signs and symptoms in the chest and recent pulmonary infiltrate in the chest X-ray [1,2]. The occurrence of CAP is influenced by geographic and seasonal factors as well as population variables such as age and the presence of underlying disease(s). Despite the availability of modern antibacterial agents and a slow decrease in the mortality rate over the last five decades, it remains a common and serious disease and is the fifth or sixth leading cause of death in countries such as the USA, the UK and Sweden.
Although the etiology of CAP continues to be investigated, it is generally agreed that Streptococcus pneumoniae is the most common cause, accounting for 30–70% of cases [3–7]. Other common pathogens include Haemophilus influenzae (2–18% of cases), Mycoplasma spp. (2–24%), Chlamydia spp. (1–3%), Legionella spp. (1–15%), Staphylococcusaureus (1–10%), Moraxella catarrhalis (1–5%), Streptococcus spp. (1–3%), Gram-negative bacilli such as Escherichia coli, Klebsiella spp. and Pseudomonas spp. (1–10%) and viruses (1–21%). Up to 10% of cases may be due to two or more aerobic bacteria, with Streptococcus pneumonia and H. influenzae being the most common combination [5,8,9].
The choice of initial antibacterial agent is usually empirical, and it should be fully effective against Streptococcus pneumoniae and other common pathogens, including the atypical, intracellular pathogens Mycoplasma and Chlamydia. The worldwide emergence of Streptococcus pneumoniae with reduced susceptibility or resistance to penicillin and macrolides, combined with the resistance problems associated with β-lactamase-producing H. influenzae and Moraxella catarrhalis, has provided a therapeutic challenge [10–12]. Penicillin-resistant pneumococci are often also resistant to macrolides and azalides. In addition, atypical pathogens are not susceptible to β-lactam antibiotics, and their susceptibility to macrolides is variable. The introduction of new antibiotics may simplify the initial treatment of CAP through broader coverage of potential pathogens and possibly by shortening the course of therapy.
Levofloxacin is the L-isomer of the racemate ofloxacin and is approximately twice as active as the equivalent amount of ofloxacin in vitro . It has a broad spectrum of activity which includes Grampositive aerobic bacteria such as Streptococcus pneumoniae and Staphylococcus aureus, Gram-negative bacteria such as Escherichia coli, H. influenzae, Klebsiella spp. and Pseudomonas aeruginosa, and atypical bacteria such as Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila [13–15]. Oral levofloxacin is rapidly absorbed with 100% bioavailability, and peak plasma concentrations are reached within 1 h. It is eliminated relatively slowly, primarily by the kidneys, with a half-life of 6–8 h, allowing once-daily dosing [16–17].
The spectrum of activity of levofloxacin, combined with its good penetration into lung tissue and bronchial secretions [18–20] and previous clinical studies [21–24], indicates that it may be effective in CAP. The aim of this study was therefore to compare the efficacy and safety of levofloxacin, at two different doses, with that of amoxycillin/clavulanic acid in the treatment of CAP in adults. Amoxycillin/clavulanic acid was chosen as the comparator because it is widely used for this indication and its efficacy is well documented [25–27].
PATIENTS AND METHODS
This was a double-blind, randomized (1:1:1), double-dummy, three-arm parallel design, multinational, multi-center study conducted in 50 centers in nine countries in patients with mild-to-moderate pneumonia. Patients were randomized to receive levofloxacin 500 mg once daily, levofloxacin 500 mg twice daily or amoxycillin/clavulanic acid 625 mg three times daily for 7–10 days. Randomization was made in blocks of six, and the study drug was randomly assigned to the patient numbers in advance within each block. The primary analysis was the clinical cure rate, determined 2–5 days after the end of treatment (post-therapy), in patients evaluable for clinical efficacy in the per-protocol population. The clinical and bacteriologic efficacy assessments, performed by the investigator and a computerized evaluation program (per-protocol assessment), were included in the efficacy analysis. The primary analysis was the per-protocol analysis determined by computer, and an intent-to-treat analysis was also performed. The study was conducted in accordance with the Good Clinical Practice Guidelines of the European Community and The Declaration of Helsinki.
In- or outpatients of either sex, aged 18–65 years, with clinical signs and symptoms of mild-to-moderate pneumonia and physical examination findings consistent with the clinical diagnosis were included in the study. Chest X-ray results confirming the clinical diagnosis of pneumonia had to be present. Patients were excluded if they were pregnant or of childbearing potential and not taking adequate contraceptive measures or if they had: pneumonia occurring more than 72 h after hospitalization; pneumonia requiring parenteral antibiotic treatment; one or more indicators of severe pneumonia; pneumonia expected to be a terminal event; glucose-6-phosphate deficiency; hypersensitivity to ofloxacin or other fluoroquinolones or penicillin/β-lactams; or any concomitant clinical condition likely to interfere with the conduct of the study. Patients were also excluded if they: required parenteral antibiotic treatment for pneumonia; had received ofloxacin or amoxycillin/clavulanic acid for this infectious episode: required probenecid or maintenance systemic corticosteroid therapy or a systemic antibiotic for another infection; or had received antibiotic pretreatment for more than 24 h in the 5 days before study entry or azithromycin in the 7 days before study entry. All patients provided written informed consent and the study protocol was approved by each local ethics committee.
Assessments were performed after 3 and 6 days of treatment, and 2–5 (post-therapy) and 14–21 days after the end of treatment. Clinical signs and symptoms of pneumonia were documented at each visit. The clinical response was defined as follows: cure (all infection signs and symptoms disappeared or returned to preinfection state and chest X-ray improved, or at least one infection-related sign and symptom, including chest X-ray, improved and no subsequent antibiotic treatment started); failure (all infection-related symptoms unchanged or worsened; new clinical findings developed consistent with active infection; death due to pneumonia; study drug discontinued because of clinical and/or bacteriologic treatment failure; one or more antibiotics added to the study drug because of treatment failure or at least one infection-related sign and symptom, including chest X-ray, improved but subsequent antibiotic treatment started) or indeterminate (circumstances precluded classification as cure or failure, e.g. missing follow-up information, premature discontinuation because of non-efficacy-related reasons, major protocol violations). Patients were withdrawn and switched to another antibiotic regimen if: the clinical response was classed as failure after at least 48 h of treatment; the bacteriologic response was unsatisfactory; or serious adverse events occurred which were possibly related to study drug.
Bacteriologic cultures were obtained from respiratory tract secretions and blood samples within 48 h before the start of treatment in order to isolate and identify the causative pathogen. The majority of respiratory tract cultures were obtained from non-invasive samples, e.g. sputum, although some were obtained by invasive methods such as bronchoscopic brushings, transtracheal aspiration and bronchoalveolar lavage. Follow-up cultures were obtained on day 3 in patients who had not responded clinically, on day 6 in the case of drug failure, 2–5 days after the end of treatment and 14–21 days after the end of treatment in the case of failure. Blood cultures were repeated in patients with persistent fever. Serum samples were also obtained at inclusion and 14–21 days after treatment for the determination of antibody titer to Mycoplasma pneumoniae, Chlamydia, Legionella and influenza viruses A and B.
The bacteriologic response was defined as: satisfactory (eradication of baseline pathogen; presumed eradication; colonization), unsatisfactory (persistence of baseline causative pathogen; relapse; superinfection; eradication and reinfection; new or additional antibiotic because of presumed persistence or resistance), or indeterminate (lack of opportunity to perform further cultures). If more than one causative pathogen was isolated from the pretreatment culture and the microbiological response was not the same for all the pathogens, the patient was classed as unsatisfactory if the response of at least one pathogen was unsatisfactory.
Safety was assessed at each visit according to adverse events and laboratory variables. Adverse events were assessed by the investigator for intensity (mild, moderate or severe), nature (serious or non-serious) and possible relationship to the study drug. Patients were withdrawn from the study immediately in the case of a serious adverse event possibly related to the study drug.
Analyses were performed on the responses in the intent-to-treat population, the per-protocol population and all patients with clinical signs and symptoms of infection excluding major protocol violators. The primary efficacy variable was the clinical cure rate, post-therapy (determined 2–5 days after the end of treatment), in the per-protocol population. Assuming a success rate of 80% in all the treatment groups and a δ of 15% (the maximum difference between the two levofloxacin groups and the amoxycillin/clavulanic acid group to be accepted as equivalent), 125 evaluable patients per group were required to provide an 80% chance (power = 80%) of having a successful trial, defined as that producing a two-sided 95% confidence interval (CI) for the difference between the clinical cure rates of the two treatments that excluded the prespecified δ value of 15% [28–30]. Each levofloxacin group was considered to be equivalent to the amoxycillin/clavulanic acid group if the upper and lower bounds of the 95% CI for the efficacy rate difference were >0% and >-15%, respectively. A comparison between the two levofloxacin groups was also performed as a complementary analysis, using the same rule as above.
In total, 1411 patients were screened, of whom 518 were included in the study, from 50 centers in nine countries. Two patients were withdrawn at their own request before the study drug was administered, so 516 patients were included in the intent-to-treat population. The demographic and baseline characteristics of the intent-to-treat population are shown in Table 1. The only statistically significant difference between the groups was a higher proportion of men in the amoxycillin/clavulanic acid group than in the levofloxacin twice-daily group (67.9% versus 57.6%; p=0.05). This difference was accounted for in the efficacy analysis of robustness.
Table 1. Demographic characteristics (intent-to-treat population)
|Mean (±SD) age (years)||41.19±15.78||40.96±14.20||40.93±14.23|
|Male||101 (59.1%)||102 (57.6%)||114 (67.9%)|
|Female||70 (40.9%)||75 (42.4%)||54 (32.1%)|
|Mean (±SD) weight (kg)||68.36±14.99||66.76±13.46||66.85±12.51|
|Race|| || || |
| White||130 (76.0%)||131 (74.0%)||124 (73.8%)|
| Black||25 (14.6%)||30 (16.9%)||29 (17.3%)|
| Asian||1 (0.6%)||1 (0.6%)||0|
| Other||15 (8.8%)||15 (8.5%)||15 (8.9%)|
|Mean BMI in kg/m2±SD||24.46±4.82||23.68±3.97||23.40±3.83|
|Diagnosis|| || || |
|emsp;Lobar pneumonia||140 (81.9%)||141 (79.7%)||131 (78.0%)|
| Bronchopneumonia||27 (15.8%)||29 (16.4%)||29 (17.3%)|
| Other||4 (2.3%)||7 (4.0%)||8 (4.8%)|
|Severity|| || || |
| Mild||82 (48.0%)||86 (48.6%)||87 (51.8%)|
| Moderate||89 (52.0%)||91 (51.4%)||81 (48.2%)|
|General condition|| || || |
| Good||131 (76.6%)||137 (77.4%)||134 (79.8%)|
| Poor||39 (22.8%)||39 (22.0%)||34 (20.2%)|
| Critical||1 (0.6%)||1 (0.6%)||0|
At inclusion, 297 (57.6%) patients had concomitant illnesses in the form of underlying diseases, of which the most frequent were respiratory, other than pneumonia. Surgical history was positive in 171 patients (33.1%), and a history of drug/alcohol abuse and smoking was observed in 14 (2.7%) and 295 (57.2%) patients, respectively. One hundred and four (20.2%) patients were receiving concomitant non-anti infective medication. Prior antibiotic treatment occurred in 54 (10.5%) patients. During treatment, 218 (42.2%) patients received concomitant non-anti-infective medications.
At inclusion, 370 patients were assigned to 7 days' treatment and 148 to 10 days' treatment. The treatment duration was prolonged to 10 days on day 6 in 72 patients originally assigned to 7 days' treatment. The mean treatment duration was 8.1 days in all three groups. Treatment was discontinued prematurely in 37 (7.2%) patients (11 in the levofloxacin once-daily group, 16 in the levofloxacin twice-daily group and 10 in the amoxycillin/clavulanic acid group). One hundred and five major protocol violations occurred in 75 patients in the intent-to-treat population, giving a per-protocol population of 441. No causative pathogen was isolated in 321 patients, so bacteriologic efficacy was assessed in 120 patients. The number of patients included in each analysis is shown in Table 2.
Table 2. Number of patients included in each analysis
|Withdrawn from the study before start of study drug||1||0||1||2|
|Excluded from per-protocol analyses||26||30||19||75|
|No pathogen isolated||105||102||114||321|
|Per-protocol+bacteriologically proven infection||40||45||35||120|
The clinical cure rates are shown in Table 3. In the intent-to-treat population post-therapy, the two-sided 95% CI for the differences in cure rates revealed therapeutic equivalence between amoxycillin/clavulanic acid and the levofloxacin once-daily (−9.7%; +6.7%) and twice-daily groups (−14.0%; +3.0%). The clinical response in the per-protocol population post-therapy as assessed by the computerized evaluation program was the primary efficacy outcome measure. The two-sided 95% CI for the differences in cure rates also revealed therapeutic equivalence between amoxycillin/clavulanic acid and the levofloxacin once-daily group (−5.7%; +5.5%) and the levofloxacin twice-daily group (−7.3%; +4.4%). A complementary analysis comparing the two levofloxacin groups did not show any difference. Of the 23 patients classed as failures, 14 improved with subsequent antibiotic.
Table 3. Clinical response post-therapy
|Intention-to-treat||No. of patients||171||177||168|
| || Cure||144 (84.2%)||142 (80.2%)||144 (85.7%)|
| || Failure||27 (15.8%)||35 (19.8%)||24 (14.3%)|
|Per-protocol||No. of patients||145||147||149|
| || Indeterminate||0||1||1|
| || Total analyzed||145 (100%)||146 (100%)||148 (100%)|
| ||Cure||138 (95.2%)||137 (93.8%)||141 (95.3%)|
| ||Failure||7 (4.8%)||9 (6.2%)||7 (4.7%)|
|Bacteriologically proven infection||No. of patients||40||45||35|
| || Cure||38 (95.0%)||42 (93.3%)||33 (94.3%)|
| || Failure||2 (5.0%)||3 (6.7%)||2 (5.7%)|
In the per-protocol population with bacterio-logically proven infection, the two-sided 95% CI for the differences in cure rates also revealed therapeutic equivalence between amoxycillin/clavulanic acid and the levofloxacin once-daily group (−12.2%; +13.6%) and the levofloxacin twice-daily group (−14.1%; +12.2%).
The clinical response post-therapy in all three populations, as assessed by the investigator, supported the findings of the computerized evaluation program. In the intent-to-treat population, the clinical cure rates were 90.6%, 87.6% and 91.1% in the levofloxacin once-daily, levofloxacin twice-daily and amoxycillin/clavulanic acid groups, respectively. In the per-protocol population, the clinical cure rates were 95.9%, 95.2% and 96.0%, respectively. The corresponding 95% CI values for levofloxacin once daily versus amoxycillin/clavulanic acid and levofloxacin twice daily versus amoxycillin/clavulanic acid were −5.3% and +5.1%, and −6.1% and +4.6%, respectively, indicating therapeutic equivalence. In the per-protocol population with bacteriologically proven infection, the cure rates were 97.5%, 93.3% and 97.1%, respectively. Evaluation of the clinical response performed at the end of the study (14–42 days after the end of treatment) also revealed no differences between the three treatment groups. Efficacy evaluations in subgroups of patients (presumed pneumococcal pneumonia; fever at baseline; lobar pneumonia; and smokers) revealed similar findings to the main analysis.
The pathogens isolated at inclusion are shown in Table 4. The majority of respiratory tract cultures were obtained from non-invasive samples; only 4.4% of patients (6/136) had invasive samples (two in the levofloxacin once-daily group, three in the levofloxacin twice-daily group and one in the amoxycillin/clavulanic acid group). Bacteremia was found in 2.3% (1/43) of levofioxacin once-daily patients, 19.6% (10/51) of levofloxacin twice-daily patients and 16.7% (7/42) of amoxycillin/clavulanic acid patients. A single pathogen was isolated in 113 patients, two pathogens in 21 patients and three pathogens in two patients. A four-fold increase in serum antibody titer between the acute and convalescent serum for atypical infections was observed in 5.8% (16/274) of patients (Mycoplasma pneumoniae eight patients, Chlamydia two, Legionella one, influenza A one and influenza B four).
Table 4. Causative pathogens isolated at inclusion in the intent-to-treat population
|Streptococcus pneumoniae||16||28||19||63 (39.1%)|
|Haemophilus influenzae||21||17||17||55 (34.2%)|
|Staphylococcus aureus||2||3||6||11 (6.8%)|
|H. parainfluenzae||3||6||1||10 (6.2%)|
|Moraxella catarrhalis||2||3||3||8 (5.0%)|
|Klebsiella pneumoniae||3||1||6||4 (2.5%)|
|Pseudomonas aeruginosa||1||1||1||3 (1.9%)|
|Enterobacter cloacae||2||1||0||3 (1.9%)|
|Proteus mirabilis||0||1||1||2 (1.2%)|
|Klebsiella oxytoca||1||0||0||1 (0.6%)|
|Streptococcus viridans||0||0||1||1 (0.6%)|
More pathogens, both Gram-positive and Gram-negative, were resistant to amoxycillin/clavulanic acid than to levofloxacin. At inclusion, using the disk diffusion method, only one (Streptococcus pneumoniae) of the 156 (0.6%) isolated pathogens tested was resistant to levofloxacin, while 14 of 138 (10.1%) pathogens tested (three Gram-positive and 11 Gram-negative (five enterobacteria and six non-enterobacteria)) were resistant to amoxycillin/clavulanic acid. None of the isolates from the levofloxacin once-daily group (0/51) and one of the 59 isolates (1.7%) from the twice-daily group was resistant to levofloxacin, while five of 40 isolates (12.5%) from the amoxycillin/clavulanic acid group were resistant to amoxycillin/clavulanic acid.
The bacteriologic response post-therapy in the per-protocol population with bacteriologically proven infection as assessed by the computerized evaluation program is shown in Table 5. All three groups showed a similar bacteriologic response rate. Similar findings were observed in the investigator's assessment of bacteriologic response (levofloxacin once daily 95.0%, levofloxacin twice daily 95.6%, amoxycillin/clavulanic acid 94.3%). The bacteriologic eradication rate by pathogen at post-therapy is shown in Table 6. All Gram-positive isolates (Streptococcus pneumoniae, Staphylococcus aureus) and all H. influenzae isolates were eradicated by all three treatments. Post-therapy, one H. parainfluenzae isolate from a multipathogen infection in a patient in the levofloxacin once-daily group and one Moraxella catarrhalis isolate in a patient in the amoxycillin/clavulanic acid group persisted. The only pathogen which was resistant to levofloxacin in the levofloxacin twice-daily group was presumed to be eradicated. Evaluation of the bacteriologic response performed at the end of the study (14 42 days after the end of therapy) also revealed no differences between the three treatment groups.
Table 5. Bacteriologic response in the per-protocol + bacteriologically proven infection population post-therapy
| Satisfactory–out of time window||0||1||1||2|
|Total analyzed||39 (100%)||43 (100%)||34 (100%)||116|
|Satisfactory||37 (94.9%)||43 (100%)||32 (94.1%)||112|
| Presumed eradication||34||36||28||98|
|Unsatisfactory||2 (5.1%)||0||2 (5.9%)||4|
| Persistence||1|| ||1||2|
| Presumed persistence||1|| ||0||1|
| Eradication+superinfection||0|| ||1||1|
Table 6. Bacteriologic eradication rate by pathogen in the per-protocol+bacteriologically proven infection population post-therapy
|Total pathogens||44/45 (97.8%)||53/53 (100%)||39/40 (97.5%)|
|Gram-negative||28/29 (97%)||28/28 (100%)||16/17 (94.1%)|
| Pseudomonas aeruginosa||1/1||1/1||1/1|
| Moraxella catarrhalis||2/2||2/2||1/2|
| Haemophilus influenzae||19/19||16/16||12/12|
| H. parainfluenzae||2/3||6/6||1/1|
|Gram-positive||16/16 (100%)||25/25 (100%)||23/23 (100%)|
| Staphylococcus aureus||1/1||3/3||6/6|
| Streptococcus pneumoniae||15/15||22/22||16/16|
All patients included in the intent-to-treat population were assessed for safety. The incidence of adverse events was similar in all three treatment groups. The incidence of adverse effects by body system is shown in Table 7. The majority of adverse events in all three groups were mild to moderate in intensity. Five events reported by four patients in the levofloxacin once-daily group, four events by four patients in the twice-daily group and six events reported by five patients in the amoxycillin/clavulanic acid group were considered by the investigator to be severe in intensity.
Table 7. Number of patients with adverse events (AEs) by body system (patients could have more than one AE)
|Total no.||171 (100%)||177 (100%)||168 (100%)||171 (100%)||177 (100%)||168 (100%)|
|Total with AEs||67(39.2%)||74 (41.8%)||71 (42.3%)||46 (26.9%)||51 (28.8%)||50 (29.8%)|
|Body as whole||11 (6.4%)||7 (4.0%)||6 (3.6%)||6 (3.5%)||1 (0.6%)||−|
|Cardiovascular||4 (2.3%)||7 (4.0%)||3 (1.8%)||−||−||−|
|Digestive||14 (8.2%)||18 (10.2%)||26 (15.5%)||11 (6.4%)||14 (7.9%)||20 (11.9%)|
|Hematologic/lymphatic||26 (15.2%)||35 (19.8%)||25 (14.9%)||23 (13.5%)||30 (16.9%)||21 (12.5%)|
|Injection site reaction||−||1 (0.6%)||−||−||−||−|
|Metabolic and nutritional||10 (5.8%)||14 (7.9%)||12 (7.1%)||6 (3.5%)||8 (4.5%)||10 (6.0%)|
|Musculoskeletal||−||4 (2.3%)||−||−||1 (0.6%)||−|
|Nervous||3 (1.8%)||4 (2.3%)||1 (0.6%)||2 (1.2%)||−||1 (0.6%)|
|Respiratory||15 (8.8%)||7 (4.0%)||17 (10.1%)||4 (2.3%)||1 (0.6%)||2 (1.2%)|
|Skin and appendages||5 (2.9%)||8 (4.5%)||6 (3.6%)||2 (1.2%)||4 (2.3%)||3 (1.8%)|
|Special senses||1 (0.6%)||1 (0.6%)||−||−||−||−|
|Urogenital||5 (2.9%)||4 (2.3%)||4 (2.4%)||−||3 (1.7%)||2 (1.2%)|
There was a low or no incidence of adverse events associated with the fluoroquinolone class of antibiotics, i.e. musculoskeletal, central nervous system, cardiovascular, digestive system, skin rash/phototoxicity and eye disorders. The majority of events in all three groups were mild to moderate in intensity.
Serious adverse events irrespective of their relationship to the study drug were reported by seven patients in the levofloxacin once-daily group (4.1%), 11 in the levofloxacin twice-daily group (6.2%) and six in the amoxycillin/clavulanic acid group (3.6%). Serious adverse events in 10 of 24 patients were considered to be possibly related to the study drug by the investigator (four in the levofloxacin once-daily group, four in the levofloxacin twice-daily group and two in the amoxycillin/clavulanic acid group).
Two deaths occurred, both in the amoxycillin/clavulanic acid group. One patient died 13 days after the end of treatment (due to tuberculosis) and the other died 2 h after the first dose of study drug (due to status asthmaticus). Treatment was discontinued in 18 patients (3.5%) due to adverse events (five in the levofloxacin once-daily group, eight in the levofloxacin twice-daily group and five in the amoxycillin/clavulanic acid group). There were no clinically relevant abnormalities in laboratory parameters.
The worldwide emergence of resistance to β-lactams and macrolides among respiratory tract pathogens has led to the reassessment of treatment for CAP [8,31]. The newer fluoroquinolones, such as levofloxacin and grepafloxacin, have good activity against respiratory tract pathogens and are well tolerated [13,32]. They should, therefore, provide a useful alternative treatment in the face of the increasing spread of resistance to traditional antibiotics .
Sparfloxacin was the first of the newer fluoroquinolones to be introduced but it has been associated with a high incidence of photosensitivity reactions and cardiovascular adverse events . In studies of CAP, sparfloxacin was shown to be as effective as the comparators, with overall efficacy rates of 92% and 87% compared with 82% for the combination of amoxycillin and ofloxacin , 80% for amoxycillin/clavulanic acid and 85% for erythromycin .
Previous studies have demonstrated the efficacy of levofloxacin in the treatment of CAP [22,23], and the results of our double-blind study confirm these findings. Our results show that levofloxacin, at a dose of 500 mg once or twice daily for 7–10 days, was equivalent to amoxycillin/clavulanic acid three times daily, in terms of efficacy, tolerability and safety for the treatment of mild-to-moderate CAP. The clinical cure and bacteriologic response rates with levofloxacin once daily (95.2% and 94.9%, respectively) and twice daily (93.8% and 100%, respectively) were equivalent to those with amoxycillin/clavulanic acid (95.3% and 94.1%, respectively) and this was confirmed by the two-sided 95% CIs for the differences in cure rates. There was no difference in therapeutic outcome between levofloxacin 500 mg once daily and twice daily.
Levofloxacin demonstrated good activity against Gram-positive pathogens, including Streptococcus pneumoniae, with a 100% eradication rate. This is an important consideration, since Streptococcus pneumoniae is the commonest cause of CAP and treatment is often empirical. Older fluoroquinolones, such as ciprofloxacin, have not been beneficial in the treatment of respiratory tract infections because of their limited activity against Streptococcus pneumoniae . The improved Gram-positive activity of levofloxacin is therefore an important advance.
Both levofloxacin and amoxycillin/clavulanic acid were well tolerated. The absence of severe cases of pneumonia in this study is reflected in the low mortality rate (0.4%), with only two deaths. Higher mortality rates of 4.5% for sparfloxacin and 2.0% for amoxycillin/clavulanic acid were reported by Lode et al in patients with non-severe, mild-to-moderate CAP . However, the same mortality rate of 0.4% was reported by Carbon et al in a study comparing temafloxacin with amoxycillin in patients with CAP of average severity .
In conclusion, the results show that levofloxacin was as effective, safe and well tolerated as amoxycillin/clavulanic acid three times daily in the treatment of mild-to-moderate CAP. In addition, levofloxacin provides the advantage of once-daily dosing. Thus, levofloxacin 500 mg once daily, for 7–10 days, is an effective and safe treatment for mild-to-moderate CAP in adults.
The authors would like to thank the following members of the international study group for their assistance in conducting this study: Argentina–Ambasch and Bergallo, Farias, Harris, Jasovich, Luna and Jolly, Mingrone, Ruvinsky; Finland—Kuosmanen, Rinne, Sanna Kesä; France—Balmes, Baron, Canton, Muir, Zuck; Germany—Cloß, Koch, Petri, Menke, Schnorr; Ireland: O'Doherty, Dwyer, McGarry, Quinn, Moran, Lee, McVey, McDonnell; Italy—Giuntini, Rizzato, Todisco; The Netherlands—Van Herzik; South Africa—Aboo and Minnie, Nel and Smit, Van Vuuren, Foden; UK—Allin, Cantor, Khong, Leak, Scott, Sheldon, Sheridan, Warriner and Spira, Rees-Jones, Northfield, Hosie. This study was supported by a grant from Hoechst Marion Roussel.