JAC Advance Access originally published online on January 30, 2006
Journal of Antimicrobial Chemotherapy 2006 57(3):536-545; doi:10.1093/jac/dki480
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Efficacy and safety of twice-daily pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg) in the treatment of adults with community-acquired pneumonia in a country with a high prevalence of penicillin-resistant Streptococcus pneumoniae
1 Emergency Room, Hospital Son Dureta, Palma de Mallorca, Spain; 2 Department of Internal Medicine, Hospital Virgen del Camino, Pamplona, Spain; 3 Medical Department, GlaxoSmithKline, Tres Cantos, Spain; 4 Infectious Diseases Unit, H. Germans Trias i Pujol, Badalona, Spain; 5 Infectious Diseases Unit, Hospital Virgen de la Victoria, Málaga, Spain; 6 Infectious Disease Service, Hospital Bellvitge, Barcelona, Spain; 7 Antibiotics, Infectious Disease MDC, GlaxoSmithKline, Greenford, UK
* Corresponding author. Tel: +34-91-807-5999; Fax: +34-91-807-0596; E-mail: rafael.dal-re{at}gsk.com
Received 1 September 2005; returned 27 October 2005; revised 23 November 2005; accepted 12 December 2005
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Abstract |
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Objectives: This randomized, double-blind, non-inferiority trial evaluated the efficacy and safety of pharmacokinetically enhanced amoxicillin/clavulanate 2000/125 mg twice daily versus amoxicillin/clavulanate 875/125 mg three times daily, both given orally for 7 or 10 days, in the treatment of adults with community-acquired pneumonia in Spain, a country with a high prevalence of penicillin-resistant Streptococcus pneumoniae.
Patients and methods: Following 2:1 randomization, 566 patients (intent-to-treat population) received either amoxicillin/clavulanate 2000/125 mg (n = 374) or amoxicillin/clavulanate 875/125 mg (n = 192).
Results: Among the patients who did not deviate from the protocol (clinical per-protocol population), clinical success at day 21–28 post-therapy (test of cure; primary efficacy endpoint) was 92.4% (266/288) for amoxicillin/clavulanate 2000/125 mg and 91.2% (135/148) for amoxicillin/clavulanate 875/125 mg (treatment difference, 1.1; 95% confidence interval, –4.4, 6.6). Bacteriological success at test of cure in the bacteriology per-protocol population was 90.8% (79/87) with amoxicillin/clavulanate 2000/125 mg and 86.0% (43/50) with amoxicillin/clavulanate 875/125 mg (treatment difference 4.8; 95% confidence interval, –6.6, 16.2). At test of cure, amoxicillin/clavulanate 2000/125 mg was clinically and bacteriologically effective against 7/7 penicillin-resistant Streptococcus pneumoniae (MIC 
2 mg/L) isolates (including three amoxicillin non-susceptible strains) and amoxicillin/clavulanate 875/125 mg against 5/5 isolates (including one amoxicillin non-susceptible strain).
Conclusions: Both treatment regimens were well tolerated. Amoxicillin/clavulanate 2000/125 mg was at least as effective clinically and as safe as amoxicillin/clavulanate 875/125 mg in the treatment of community-acquired pneumonia in adults in a country with a high prevalence of penicillin-resistant S. pneumoniae and has a more convenient twice daily posology.
Keywords: anti-infective development , antimicrobial therapy , ß-lactams
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Introduction |
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Community-acquired pneumonia (CAP) is a common disease with a high economic burden and is associated with significant morbidity and mortality, particularly among older adults and those with co-morbid risk factors.1 Streptococcus pneumoniae is the most common aetiological organism; however, Haemophilus influenzae and Moraxella catarrhalis are also frequently isolated.2
The recent changes in the susceptibility of S. pneumoniae and other respiratory pathogens to antibacterial agents are a cause for clinical concern.3 The prevalence of penicillin-resistant S. pneumoniae (PRSP; MIC 2 mg/L) in Spain has been reported to range from 20 to 35% in the last decade4–6 and resistance to other antibacterials, including cephalosporins, macrolides, azalides, sulphonamides and tetracyclines, has also been noted.3,7 Besides, resistance to other antibiotics tends also to be higher in penicillin-resistant isolates (resistance to erythromycin reaches 55–60% among penicillin-resistant strains).4–6
Guidelines for the management of CAP have recently been published, which stress the need to take into account S. pneumoniae isolates with resistance to antibacterial agents.8,9 Among patients with CAP who survived the first few days after hospitalization, increased rates of mortality due to S. pneumoniae with high resistance to penicillin have been reported, but this association has not yet been clearly demonstrated.10,11
Amoxicillin/clavulanate has been in clinical use for over 20 years; it consists of the broad-spectrum ß-lactam, amoxicillin and the ß-lactamase inhibitor clavulanate. Although it has been very effective in the past, the emergence of S. pneumoniae isolates with increased MICs to amoxicillin/clavulanic acid (4/2 mg/L)12,13 indicates the need for improved approaches to antibacterial therapy.
In Spain, the existence of S. pneumoniae isolates with reduced susceptibility to penicillin14 has led to the introduction of a three-times-daily regimen of amoxicillin/clavulanate 875/125 mg for adult CAP empirical treatment, in order to achieve a higher T > MIC than the twice-daily regimen that is used elsewhere.
A new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg given in two 1000/62.5 mg tablets twice daily) has recently become available.15 This new formulation can maintain the mean amoxicillin serum concentration >4 mg/L for 
49% of the dosing interval in contrast with only 34% for the three-times daily regimen.15,16 The pharmacodynamic and pharmacokinetic properties of the new formulation predict high rates of success against respiratory tract pathogens, including PRSP and S. pneumoniae isolates with resistance to amoxicillin (MIC 
4 mg/L).16
This study investigated whether oral treatment twice daily with the pharmacokinetically enhanced formulation of amoxicillin/clavulanate 2000/125 mg is at least as effective as oral treatment with amoxicillin/clavulanate 875/125 mg, given three times daily in adults with CAP of suspected pneumococcal origin. The safety profile of both treatments was compared.
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Patients and methods |
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Study design
This randomized, multicentre, double-blind, double-dummy parallel group study compared the efficacy and safety of oral amoxicillin/clavulanate 2000/125 mg twice daily (the experimental group; Group E) with oral amoxicillin/clavulanate 875/125 mg three times daily (the control group; Group C) for the treatment of adults with CAP of suspected pneumococcal origin based on clinical criteria for ‘typical’ bacterial pneumonia. The primary objective was to demonstrate the non-inferiority of amoxicillin/clavulanate 2000/125 mg twice daily to amoxicillin/clavulanate 875/125 mg three times daily.
The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki principles. Approval was obtained from the Research Ethics Committee of all participating centres. Written and dated informed consent was obtained from each subject before enrolment.
Patients were randomized 2:1 to receive either: (i) amoxicillin/clavulanate 1000/62.5 mg (two tablets twice daily) plus matching amoxicillin/clavulanate 875/125 mg placebo (one tablet three times daily) [Group E]; or (ii) amoxicillin/clavulanate 875/125 mg (one tablet three times daily) plus matching amoxicillin/clavulanate 1000/62.5 mg placebo (two tablets twice daily) [Group C]. Study medication was taken before meals for either 7 or 10 days, depending on the severity of CAP infection as assessed at the on-therapy visit and co-morbid factors. Subjects were treated on an outpatient basis or in hospital, as appropriate. Mortality risk was classified according to the criteria defined by Fine et al.17
Eligibility criteria
Adults (18 years of age) were eligible for inclusion in the study if they had a clinical diagnosis of CAP, radiologically confirmed by a chest radiograph performed at screening or within 48 h before enrolment, showing evidence of new or progressive infiltrate(s) or consolidation consistent with pneumonia. Patients should have had fever or recent history of fever or hypothermia and at least one of the following signs/symptoms: new or increased cough; purulent/changed sputum characteristics; auscultatory rales and/or evidence of pulmonary consolidation; dyspnoea or tachypnoea; elevated total peripheral white blood cell count (>10 000 cells/mm3), >15% immature neutrophils or leucopenia (<4500 cells/mm3); hypoxaemia with PO2 <60 mmHg (breathing room air) or oxygen saturation of <90% by pulse oximetry; and suspicion of pneumococcal origin based on at least one of the following criteria: sudden onset (<48 h), chills, pleuritic chest pain and localized alveolar consolidation on radiography. Female patients of child bearing potential were required to provide a negative urine pregnancy test.
Subjects excluded were those with a positive Legionella Urine Antigen test; with known or suspected hypersensitivity to ß-lactams; with suspected viral, atypical, hospital-acquired, aspiration or post-obstructive pneumonia (but not subjects who had a chronic obstructive pulmonary disease); with cystic fibrosis, active tuberculosis, bronchiectasis, active pulmonary malignancies or active infectious mononucleosis; those who required parenteral antibacterials, had signs of disseminated or complicating infection/disease that would compromise treatment evaluation; who had received >24 h treatment with any antibacterial agent for this episode of CAP in the week before randomization; with known or suspected renal impairment and/or creatinine clearance of <30 mL/min, known or suspected hepatic impairment or alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase x3 ULN or bilirubin levels x1.5 ULN, at the screening visit, or with a history of amoxicillin/clavulanate-associated jaundice/hepatic dysfunction; with immune defects or who were HIV positive (CD4 <200 cells/mm3); with life threatening or serious, unstable underlying condition; who were concurrently receiving treatment with tubular secretion inhibitors or had received pneumococcal polysaccharide vaccine within 30 days prior to inclusion or were treated with any investigational drug/vaccine/device within 30 days prior to screening; with active alcohol or drug abuse; or who had previously been enrolled in this study. Females who were pregnant or lactating or who failed to use adequate contraception methods throughout the study were also excluded.
Efficacy variables: clinical, radiological and bacteriological assessments
Patients were required to attend the clinic four times: day 0 (screening), day 3–5 (on-therapy), day 9–14 (i.e. 2–4 post-therapy) (end of therapy; EOT) and day 28–38 (i.e. 21–28 post-therapy) (test of cure; TOC). The primary efficacy variable in this study was clinical response at TOC in the clinical per-protocol population. Clinical and bacteriological responses at EOT and bacteriological and radiological responses at TOC were secondary efficacy variables. Clinical outcome at EOT and TOC was defined as ‘success’ when there was sufficient resolution of CAP such that no additional antibacterial therapy for CAP was indicated. The clinical outcome of ‘failure’ at TOC comprises the reappearance or deterioration of CAP following clinical success at EOT (clinical recurrence), the clinical failure at EOT and the instances when the assessment could not be made.
Clinical outcome at TOC was evaluated only for patients who were considered clinical successes at EOT. Clinical failures at any visit were classified as failures at all subsequent time-points.
Radiological outcome was evaluated at TOC (or at EOT for early withdrawals or clinical failures at EOT) by comparing postero–anterior and lateral view chest radiographs with the baseline radiographs. Patients whose radiographs showed improvement from baseline were radiological successes, while those whose radiographs showed worsening or no changes from baseline were radiological failures. If radiological outcome could not be determined from the repeat radiograph, success or failure was presumed based on clinical response.
Patients provided a sputum sample, or an invasive respiratory sample when clinically indicated, as well as two blood culture samples at screening. Respiratory samples were also collected at EOT and TOC when possible, if clinically indicated, or when the subject had withdrawn. Sputum samples were evaluated for purulence (>25 WBCs per field and <10 squamous epithelial cells per field at x100 magnification). If the sputum sample was not purulent the sample was not cultured for bacteriology.
Subjects with positive blood culture at screening, or if clinically indicated, were to have repeat blood samples taken for bacteriological evaluation at the on-therapy visit and at EOT if samples remained positive.
Blood and respiratory sample culture and preliminary identification of organisms were conducted at the hospital laboratory. When a respiratory pathogen was isolated, the strain was sent to a central laboratory (Quest Diagnostics, Heston, UK) for confirmation of identification and microdilution susceptibility testing.18–20 As NCCLS breakpoints for the new 16:1 formulation (2000/125 mg) used in this study had not been determined, the NCCLS breakpoints for conventional Augmentin formulations (i.e. 875/125 mg twice daily) were applied, defined as: susceptible, 2/1 mg/L; intermediate, 4/2 mg/L; and resistant, 8/4 mg/L. ß-Lactamase testing was provided for Haemophilus spp., M. catarrhalis, Enterococcus spp. and Staphylococcus aureus. Acute and convalescent phase serological assays for atypical pathogens (Mycoplasma pneumoniae, Coxiella burnetii, Chlamydia spp., Legionella pneumophila) were performed on paired samples at a central laboratory (MRL Diagnostics, Cypress, CA, USA). Current or recent infection with an atypical pathogen at screening was assessed as follows: (a) M. pneumoniae, IgG testing with a ratio of 1.1 at TOC and rise of 46% between screening and TOC, or IgM with a ratio of 1.1 at screening and/or TOC, by ELISA (Wampole Laboratories); (b) Coxiella burnetii, IgG phase II titre of 1:256 at screening and/or TOC, IgG or IgM titre of 1:16 (phases I and II) and phase II titres > phase I titres (this criterion could be met at screening and/or TOC), or 4-fold rise in IgG or IgM phase II titre between screening and TOC, with a TOC phase II titre 1:64 by indirect fluorescent antibody (MRL Diagnostics); (c) Chlamydia spp., a 4-fold rise in IgG titre between screening and TOC or IgG titre 1:16, IgM titre 1:10 and IgA titre 1:16 in a single visit, by microimmunofluorescent antibody (MRL Diagnostics); (d) L. pneumophila, a 4-fold increase in antibody titre between screening and TOC by indirect fluorescent antibody (Zeus Scientific).
The bacteriological response was evaluated at EOT (first post-therapy visit) or TOC (second post-therapy visit) as follows: bacteriological success was defined as ‘eradication’ (absence of all initial typical pathogens) or ‘presumed eradication’ (clinical success in the absence of an evaluable sample) with ‘no superinfection or new infection’ (no new pathogen identified in a symptomatic patient); bacteriological failure was defined as ‘persistence’ of one or more initial pathogens in a bacteriological sample, ‘presumed persistence’ (clinical failure in absence of an evaluable sample), ‘bacteriological recurrence’ (pathogen recurred at test of cure), ‘superinfection or new infection’ (as defined above) or ‘unable to determine’ (result not confirmed in central laboratory or, in absence of evaluable sample, a clinical assessment could not be made).
Identification of a new pathogen in an asymptomatic patient was defined as colonization and was not classified as bacteriological failure.
Safety assessments
Adverse events were recorded at all visits for the purpose of assessing safety, regardless of their possible relationship to study medication. Any adverse event that was fatal, life threatening, disabling or incapacitating, resulted in a prolonged hospital stay, or was associated with cancer or overdose was to be considered a serious adverse event. Any other event considered by the investigator to be serious was also recorded as a serious adverse event. Patients were monitored for clinical and laboratory adverse events during therapy and for 30 days post-therapy. All laboratory parameters were measured by the central laboratory (Quest Diagnostics, Heston, UK).
Statistical analysis
For both primary and secondary efficacy parameters, analyses were based on an unstratified comparison of proportions between the treatment groups for the clinical per-protocol (PP) population. The robustness of the principal analyses was assessed from the re-analyses using the intent-to-treat (ITT) population for both primary and secondary efficacy parameters. Two-sided 95% confidence intervals (CI) were used to estimate the difference in the proportion of successes between treatment groups, calculated using the normal approximation to the binomial distribution. A conclusion of non-inferior efficacy of amoxicillin/clavulanate 2000/125 mg (Group E) was drawn if the lower limit of the 95% CI was –10%.
In order to achieve a power of 90%, the study required 426 evaluable patients, assuming an underlying equivalent clinical response rate of 90%. It was anticipated that up to 25% of randomized subjects would be ineligible for the clinical PP population at TOC; therefore, 569 patients were to be recruited (379 and 190 patients for Groups E and C, respectively).
Population sets were defined and analysed. The ITT population included all patients who took at least one dose of study medication; this population was also used for the safety analysis. The clinical PP population was a subset of the ITT population, and excluded patients who violated any aspect of the protocol that would affect the assessment of efficacy; this was the primary population of interest. The bacteriology ITT population included all randomized patients who took at least one dose of study medication and had at least one pre-therapy typical pathogen identified at screening. The bacteriology PP population was a subset of the bacteriology ITT population, and excluded patients who violated any aspect of the protocol that would affect the assessment of efficacy.
For the analysis of withdrawal and safety data (adverse events which occurred in 5% of patients in either treatment groups) the proportions of patients were compared between treatment groups using Fisher's exact test. Two-sided 95% confidence intervals (CIs) were used to estimate the difference in proportions between the treatment groups. The CIs were calculated using the normal approximation to the binomial distribution.
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Results |
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Disposition of subjects
The study patient population is presented in Table 1. A total of 569 subjects were randomized at 32 centres in Spain between October 2001 and November 2003, and 566 received at least one dose of study medication (ITT population). Among the ITT population, 374 patients were randomized to the experimental Group (E) and 192 to the control Group (C). A total of 475 (84%) patients in the total ITT population completed the study. Main reasons for withdrawal were insufficient therapeutic effect and adverse event, with no significant differences between the treatment groups. Treatment compliance was 90% in both treatment groups.
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There were no major differences between treatment arms in the incidence of protocol violations which led to exclusion of the patients from the clinical PP population. The most frequent protocol deviations in both groups were lack of compliance with study medication, visit compliance and patients for whom clinical outcome could not be determined.
No significant differences were observed in the baseline demographics (ITT population) or in the signs and symptoms of CAP (clinical PP population at TOC) between the two treatment groups. Most ( 88%) of the subjects in each treatment group had a low risk for mortality as published by Fine, with very few (<2%) in high risk category (Table 2).
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Bacteriology at screening
Approximately 55% of patients in the ITT population provided an evaluable sputum sample each at screening. Additionally, one patient in Group E and one patient in Group C had a respiratory sample obtained by invasive methods (by thoracocentesis and pulmonary puncture, respectively). The bacteriological ITT population comprised subjects with at least one pre-therapy typical pathogen identified at screening: 102/376 (27%) in Group E and 56/193 (29%) in the Group C (Table 1). The most common typical pathogen identified in both groups was S. pneumoniae, which was isolated from 73/102 (72%) and 32/56 (57%) patients, respectively (Table 3). In the bacteriology ITT population, 16 (out of 158) patients were infected with ß-lactamase-producing strains of H. influenzae, H. parainfluenzae, methicillin-susceptible S. aureus and M. catarrhalis.
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Among the bacteriological PP population, at least one typical pathogen was isolated from 94 (25%) patients in Group E and from 52 (27%) in Group C at EOT (Table 1). S. pneumoniae was the most commonly identified pathogen (Table 3), isolated in 72% (68/94) of patients in Group E and in 58% (30/52) of patients in Group C.
There were small differences between the treatment groups in the proportions of pathogens identified, with a slightly higher proportion of S. pneumoniae isolated in Group E than in Group C. No differences were noted between treatment groups in the antibacterial susceptibilities of S. pneumoniae and H. influenzae isolates.
Eight penicillin-resistant S. pneumoniae (MIC 2 mg/L; PRSP) isolates were identified at screening in seven patients in Group E, including three amoxicillin non-susceptible strains (with MICs of 4, 8 and 16 mg/L, respectively). One of these patients with one amoxicillin-susceptible isolate was excluded from the bacteriology PP at TOC. Five PRSPs were isolated in four patients in Group C, including one amoxicillin-resistant pathogen (MIC = 8 mg/L).
The percentage of S. pneumoniae bacteraemias at screening in the bacteriology PP population was 26% (24/94) in Group E, including three PRSP, and 21% (11/52) in the comparator group, including two PRSPs. All of the S. pneumoniae strains were susceptible to amoxicillin.
M. pneumoniae, C. burnetii and C. pneumoniae were the most frequently identified atypical pathogens by serology. In the bacteriological PP, 8.5% patients had a mixed (typical and atypical pathogen) infection. The overall proportion of patients who only had an atypical pathogen diagnosed was 26% (113/436); these patients were not included in the bacteriology PP population.
Clinical and radiological efficacy
The primary and secondary efficacy parameters are detailed in Table 4. Clinical success rates at TOC in the clinical PP population, the primary efficacy variable, were similar: 92.4% with amoxicillin/clavulanate 2000/125 mg (Group E) and 91.2% with amoxicillin/clavulanate 875/125 mg (Group C) (percentage treatment difference 1.1; 95% CI –4.4, 6.6).
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The clinical success rates achieved in the clinical PP population at TOC for patients with low mortality risk (Risk Class I–III) were the same: 92% for both treatment groups (232/253 in Group E and 121/132 in Group C) and for patients with high mortality risk, as published by Fine (Class V), 100% in both arms (5/5 and 1/1, respectively). Success rates for those subjects with a moderate mortality risk (Risk Class IV) were 97% (29/30) in Group E and 87% (13/15) in Group C.
Among patients with bacteraemia, the clinical success rate at TOC in the clinical PP population was 92% (22/24) in Group E and 85% (11/13) in Group C. All bacteraemic patients who had PRSP infection (three in Group E and two in Group C) were clinical successes at TOC. Similarly all the ß-lactamase-producing strains of H. influenzae (five in Group E and two in Group C) were clinical successes at TOC.
There was little difference between treatment groups for all other secondary efficacy parameters (Table 4). In the clinical ITT population, clinical response success rates at TOC were 84 and 82% in Groups E and C, respectively. Clinical success rates in the clinical ITT bacteraemic patients at TOC were 86 (24/28) and 80% (12/15), respectively. As expected, clinical success rates were slightly lower in the clinical ITT population as patients with a clinical outcome assessed as ‘unable to determine’ were classified as failures.
In both the clinical PP and ITT populations, the treatment difference in clinical response was no less than the tolerable limit of –10%.
At TOC, clinical success rates for patients with atypical pathogens in either the clinical PP population or in the ITT population were similar for both treatment groups (Table 5).
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There were no differences in the radiological responses in the two populations (PP, ITT) between both treatment groups (Table 4).
Bacteriological response
There were no differences in the bacteriological success rates (eradication or presumed eradication), either at EOT or TOC, in the bacteriology PP population between treatment arms (Table 6). At EOT, most patients with S. pneumoniae were bacteriological successes (97 and 93% in Groups E and C, respectively), as were those with H. influenzae (95 and 91% in Groups E and C, respectively). At TOC, the bacteriological success rates against S. pneumoniae were 97% in Group E and 90% in the control group, and were 90 and 80%, respectively, for H. influenzae. Only one patient in Group E experienced a new infection (with H. influenzae) at EOT. No infections with new pathogens were identified at TOC. Due to clinical improvement very few patients provided subsequent evaluable sputum sample at other study visits.
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Bacteriological success among bacteraemic patients at TOC was 92% (22/24) in bacteriology PP Group E and 85% (11/13) among Group C patients.
Isolates of S. pneumoniae among the bacteriology PP population with reduced susceptibility or resistance to penicillin, erythromycin, trimethoprim/sulfamethoxazole or cefuroxime were associated with a 100% of bacteriological success at TOC in both treatment groups. All PRSP (including the four amoxicillin non-susceptible strains) identified in the study were eradicated or presumed eradicated at both EOT and TOC. All five patients with ß-lactamase-producing H. influenzae in Group E were bacteriological successes at both EOT and TOC. In Group C, both patients with ß-lactamase-producing H. influenzae were clinical and bacteriological successes at EOT. At TOC, however, one patient, despite being a clinical success, was a bacteriological failure (Table 6).
Safety
Most subjects received the prescribed course of either 7 days (64 and 58% in Groups E and C, respectively) or 10 days (23 and 28% in Groups E and C, respectively). Only 1.6% of cases in the experimental group (E) and 0.5% in the control arm group (C) received 11 days of treatment.
The safety data refer to the on-therapy and the 30 days post-therapy period. During this interval, 51% (189/374) of patients in Group E ITT population reported at least one adverse event, as did 53% (102/192) in the control arm. Adverse events were generally mild to moderate in severity and the majority were reported between 0 and 5 days after the commencement of therapy. The most common adverse event reported was diarrhoea, in 12% (44/374) patients in Group E and in 12.5% (24/192) in Group C. There were no differences between groups in the incidence of withdrawals due to adverse events (including serious adverse events): 3% (12/374) patients in Group E versus 5% (10/192) in Group C (Table 7).
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In Groups E and C, 63 (17%; 63/374) and 28 (15%; 28/192) patients, respectively, reported an adverse event considered by the investigator to be of suspected or probable relationship to study drug. Diarrhoea was the most frequently reported drug-related adverse event, occurring in similar proportions in each treatment group (E: 10.2%; n = 38 versus C: 9.9%; n = 19). Abdominal pain was reported in 2.7% (n = 10) in the E group versus 2.6% (n = 5) in the C group. Finally, an increase in ALT was documented in 1.3% (n = 5) in Group E and in 0.5% (n = 1) in Group C.
The incidence of serious adverse events was comparable between both groups: 6% (23/374) in Group E and 8% (16/192) in Group C. Only one case of nausea in Group E and two cases of diarrhoea in Group C were considered by the investigator to be probably related to study medication and only one of the diarrhoea cases led the investigator to withdraw the patient from the study. There were three (two in Group E) deaths in the 30 day post-therapy period; none were considered to be related to study medication.
In laboratory analyses, more patients in the experimental Group E had raised ALT and AST levels than in the comparator Group at EOT (ALT 4.3% versus 0.5% and AST 2.6 versus 0.5%; retrospective statistical testing is not considered appropriate due to multiplicity and lack of power). No further laboratory tests were available for these patients. None of the patients were withdrawn from the trial due to these laboratory abnormalities (Table 7) and in only six cases the investigator assessed the event as being related or probably related to the study drug.
The increased dose of amoxicillin contained in the experimental formulation (amoxicillin/clavulanate 2000/125 mg) could have the potential risk of crystalluria (renal excretion route). Patients had an on-therapy visit urinalysis test, which showed that no crystals, others than those routinely seen in urine, were reported for the study patients.
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Discussion |
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An appropriate match of the patient and empirical regimen is of utmost importance in the treatment of CAP. Knowledge of local epidemiology is increasingly important with the increase of S. pneumoniae resistance to ß-lactams, macrolides, fluoroquinolones, tetracyclines and sulphonamides.
This study shows that amoxicillin/clavulanate 2000/125 mg twice daily was at least as effective clinically as amoxicillin/clavulanate 875/125 mg three times daily for the treatment of adults with CAP of suspected pneumococcal origin. The lower limit of the 95% CI for the difference in clinical response rates at TOC was > –10%, confirming that the primary efficacy endpoint had been achieved. Primary findings were also supported by the secondary efficacy endpoints. This study was not designed to demonstrate non-inferiority for secondary endpoints, but the clinical and bacteriological success rates at TOC and EOT were highly comparable for both treatment groups. The difference in isolation rates for S. pneumoniae between the E and the C groups was almost statistically significant. Fortunately, this ‘bias’ goes against the hypothesis, as those with positive cultures could be considered to have more severe infections.
Bacterial eradication is important as it has been shown to correlate with improved clinical outcome and a reduced incidence of recurrence in respiratory tract infections; in addition, eradicating the pathogen may reduce the risk of resistance developing and resistant pathogens being disseminated.21–23 Elimination of the causative pathogen, including resistant isolates, is a key goal of antimicrobial therapy for CAP.21 In a recent meta-analysis of 10 respiratory tract infection studies with a total of 1295 patients (bacteriology per-protocol population) receiving amoxicillin/clavulanate 2000/125 mg twice daily showed a combined bacteriological success rate against PRSP of 96% (50/52 isolates), including 6/7 with amoxicillin MICs of 4 mg/L and 7/8 with amoxicillin MICs of 8 mg/L.24 Furthermore, amoxicillin/clavulanate 2000/125 mg twice daily was highly effective against PRSP also resistant to erythromycin [97% (34/35) success rate].24 As a ß-lactam, the bactericidal activity of amoxicillin is largely dependent on time above MIC (t > MIC). For amoxicillin/clavulanate, a t > MIC of 35–40% of the dosing interval is predictive of high bacteriological efficacy.25 Amoxicillin/clavulanate 875/125 mg is given twice daily in most countries; however, this schedule offers a t > MIC of <35% of the dosing interval for pathogens with an amoxicillin MIC of 4 mg/L. The three-times-daily regimen increases t > MIC to 34% of the dosing interval for S. pneumoniae isolates with an MIC of 4 mg/L.15,16 In Spain, the prevalence of S. pneumoniae with amoxicillin MICs 4 mg/L has been reported as 5–10%.4–6
In this study, almost all pathogens were eradicated or presumed eradicated at the EOT visit with few pathogens persisting (<2%) or presumed persisting (7%). Both treatment arms were completely successful against S. pneumoniae strains that were either resistant or of intermediate susceptibility to penicillin, erythromycin or other antibacterials tested. Amoxicillin/clavulanate 2000/125 mg twice daily achieved high rates of clinical and bacteriological success against resistant isolates, including 7/7 PRSP (penicillin MIC 2 mg/L) isolates (3/3 isolates with amoxicillin MIC 4 mg/L). In the amoxicillin/clavulanate 875/125 mg three-times-daily group, clinical and bacteriological success at TOC were achieved against 5/5 PRSP, including 1/1 isolate with an amoxicillin MIC of 4 mg/L. In addition, amoxicillin/clavulanate 2000/125 mg twice daily was effective against all isolates of ß-lactamase-producing H. influenzae.
The clinical and bacteriological success rate in subjects with positive blood cultures at screening was high in both groups and all bacteraemic subjects who had PRSP infections were clinical and bacteriological successes at TOC.
The efficacy data from this study are in line with previously published data for amoxicillin/clavulanate 2000/125 mg twice daily in CAP, in which the clinical success rates at TOC have ranged from 90.3 to 94.7%, whereas the bacteriological success rates were 85 and 90.6%.26–28 These success rates were slightly lower when the ITT populations are considered: 81.1–85.1% and 70–84.1% for the clinical and bacteriological success rates, respectively.26–28
Interestingly, the proportion of S. pneumoniae that were penicillin resistant (MIC 2 mg/L) was quite low in this study (12%), compared with the reported prevalence of PRSP in Spain (20%).6 One possible reason for this is that patients with serious underlying disease and those who had recently received antibacterial therapy were excluded from this study; such patients could be at risk of developing infection with resistant pathogens. An inverse relationship between virulence and resistance is clearly acknowledged in animal models.29 In this sense, when surveillance studies exclusively target invasive S. pneumoniae strains, the resultant resistant rates tend to be somewhat lower (9.2–12.7%)30,31 than when strains from patients with COPD are also included.4–6
Clinical success at TOC in the clinical PP population for both treatment groups was within the range of 89–94% for patients with serological evidence of recent or current infection with atypical pathogens. This high clinical success rate indicates that the prior or concomitant presence of one or more atypical pathogens does not impair the efficacy of either amoxicillin/clavulanate formulations in the treatment of CAP. Besides, Legionella was excluded by the protocol. Another possible explanation for the high clinical success rates among subjects with ‘atypical pathogens’ is that even though subjects have symptoms considered to be of presumed ‘typical aetiology’ there may be a high spontaneous cure rate in this population, which in turn casts doubts as to whether there is a specific need for coverage of these atypicals other than an adequate ß-lactam active against the perilously pyogenic bacteria.32
Amoxicillin/clavulanate 2000/125 mg twice daily and amoxicillin/clavulanate 875/125 mg three times daily were both well tolerated in this study, with safety profiles consistent with the known pharmacological effects of both formulations of the drugs. The most frequent adverse events were diarrhoea and headache; there were no significant differences between the amoxicillin/clavulanate formulations for these events.
In conclusion, twice-daily therapy with oral pharmacokinetically enhanced amoxicillin/clavulanate 2000/125 mg was at least as effective as three-times-daily oral amoxicillin/clavulanate 875/125 mg for the treatment of CAP with clinical criteria of typical pneumococcal aetiology and high likelihood of pneumococcal involvement. The treatment was well tolerated, with no unexpected adverse events. The pharmacokinetically enhanced formulation offers efficacy against PRSP, including isolates with an amoxicillin MIC of 4 mg/L, while maintaining coverage of ß-lactamase-producing pathogens, and provides a valuable treatment option for empirical therapy of adults with CAP in countries, such as Spain, with high prevalence rates of PRSP. The twice-daily regimen of amoxicillin/clavulanate 2000/125 mg is likely to be more convenient for patients than the three-times-daily regimen.
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No declarations were made by the authors of this paper.
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Members of the 620 Clinical Study Group include A. Adrover and J. Vidal, Hospital Son Dureta, Palma de Mallorca; J. M. Aguado, Hospital Doce de Octubre, Madrid; R. Agüero, Hospital Marqués de Valdecilla, Santander; L. Aguilar and C. García-Rey, GlaxoSmithKline, Tres Cantos; R. Arjona, Hospital Sierrallana, Torrelavega; S. Bardagí and P. Barrufet, Hospital Mataró, Barcelona; R. Blanquer, Hospital Dr. Peset, Valencia; C. Bravo, Hospital Valle de Hebrón, Barcelona; I. Carrasco, Hospital Municipal, Badalona; F. Condés, Quest Diagnostics, Madrid; J. Custardoy, Hospital Vega Baja, Alicante; L. De Teresa and C. Mirete, Hospital San Vicente del Raspeig, Alicante; J. De la Torre, Hospital Costa del Sol, Marbella; J. De la Torre, Hospital Reina Sofía, Córdoba; J. Duran, Hospital Txagorritxu, Vitoria; M. Falguera, Hospital Arnau de Vilanova, Lleida; J. Garau, Hospital Mutua de Terrassa, Terrassa; A. Gil Aguado, Hospital La Paz, Madrid; J. Gómez, Hospital Valme, Sevilla; M. Górgolas, Fundación Jiménez Díaz, Madrid; I. Grau, Hospital Bellvitge, Barcelona; J. Hernández, Hospital San Cecilio, Granada; L. Molinos, Hospital Central Asturias, Oviedo; J. Pachón, Hospital Virgen del Rocío, Sevilla; R. Palacios, Hospital Virgen de la Victoria, Málaga; J. Picazo, Hospital Clínico, Madrid; S. Pérez, Hospital Jerez, Jerez; E. Reynaga, Hospital Germans Trias i Pujol, Badalona; M. Rivas and F. J. Suárez, Hospital Clínico, Zaragoza; M. J. Sánz and I. Wilhelmi, Hospital Severo Ochoa, Leganés; J. Sesma, Hospital Virgen del Camino, Pamplona; V. Sobradillo, Hospital Cruces, Bilbao; J. L. Viejo, Hospital General Yagüe, Burgos; G. Zubillaga, Hospital de Donostia, San Sebastián; Spain, and Rachel Hodge and Veena Kalia, GlaxoSmithKline, Greenford, United Kingdom.
This work received financial support from GlaxoSmtihKline, Greenford, UK.
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