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Article
Vol. 11. No. 2
Eur. J. Clin. Microbiol. Infect. Dis., February 1992, p. 118-124 0934-9723/92/02 0118-07 $ 3.00/0
Cefuroxime and Cefuroxime Axetil versus Amoxicillin plus Clavulanic Acid in the Treatment of Lower Respiratory Tract Infections
C. Brambilla 1, S. Kastanakis 2, S. Knight 3, K. Cunningham 3.
In a large multinational study, the clinical and bacteriological efficacy of intravenous cefuroxime 750 mg t.i.d, followed by oral cefuroxime axeti1500 mg b.i.d, was compared to that of amoxiciilin plus clavulanic acid (CA) administered as 1.2 g intravenously t.i.d, followed by 625 mg orally t.i.d, in the treatment of lower respiratory tract infections in hospitalised patients. A total of 512 patients were entered (256 in each treatment group). All were suffering from pneumonia or acute exacerbations of chronic bronchitis or bronchiectasis and required initial parenterai antibiotic therapy. Parenteral therapy lasted 48 to 72 h and was followed by five days of oral therapy. The clinical responses in the two treatment groups were very similar:. 223 of 256 (87.1%) patients were cured or improved with cefuroximelcefuroxime axetU compared to 220 of 256 (85.9 %) with amoxicillin/CA. Positive pre-treatment sputum samples were obtained from 44 % of the patients. Clearance rates obtained were again similar:. 72.8 % with cefuroxime/cefuroxime axetii and 70 % with amoxicillin/CA. Ten percent of the isolates were beta-lactamase producers, similar numbers of which were cleared in both groups. Both regimens were generally well tolerated, with only 5 % of patients treated with the cefuroxime regimen and 4.3 % of patients treated with amoxicillin/CA experiencing drug-related adverse events. Cefuroxime/cefuroxime axetU "follow-on" therapy produces clinical and bacteriological efficacy equivalent to that of amoxiciilin/CA, with the advantage of twice daily oral administration.
Lower respiratory tract infection is a common cause of morbidity, particularly during the winter months. Some patients require admission to hospital, where treatment is generally initiated with a parenterally administered antibiotic. Converting the treatment of such patients to an orally absorbed formulation of the same compound offers the potential of early discharge from hospital. This is a major benefit to the patient and may result in overall savings in the cost of treating such patients. Cefuroxime is an injectable cephalosporin antibiotic with a broad spectrum of antibacterial activity and a high degree of stability against betalactamases produced by gram-negative organisms and staphylococci (1-3). It has been found to be 1Centre Hospitalier Regional et Universitaire, Grenoble, France. 2General Hospital, Chania, Crete, Greece. 3Glaxo Group Research, Greenford Road, Greenford, UK.
effective in a wide range of infectious conditions, including lower respiratory tract infections. Oral cefuroxime sodium is only minimally absorbed and therefore until recently has been limited to intravenous use in hospitalised patients. Cefuroxime axetil is a prodrug of cefuroxime which has been developed for oral administration. It is rapidly hydrolysed in the intestinal mucosa, liberating cefuroxime which is absorbed into the blood. Bioavailability studies indicate that 50 to 60 % of the administered dose of cefuroxime axetil is absorbed when administered after a meal (4, 5; A.B. Straughn et al., 24th ICAAC, 1984, Abstract 592). A 500 mg dose yields peak serum cefuroxime concentrations of 7-10 mg/1 after two to three hours (5-7). It has been shown to penetrate rapidly into sputum and bronchial tissue, producing levels that exceed the MICs for pathogens most frequently associated with lower respiratory tract infections (8; R. Wise et al., 4th European Congress of Clinical Microbiology, 1989, Abstract 762). Cefuroxime has
Vol. 11, 1992
g o o d in v i t r o a c t i v i t y a g a i n s t t h e m a j o r r e s p i r a t o r y p a t h o g e n s such as Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis, KlebsieUa pneumoniae a n d Staphylococcus aureus. The combination of amoxicillin and the beta-lact a m a s e i n h i b i t o r c l a v u l a n i c a c i d ( C A ) is also active a g a i n s t s t r a i n s r e s i s t a n t to p e n i c i l l i n a n d is a v a i l a b l e b o t h as a n i n t r a v e n o u s a n d o r a l formulation. This s t u d y w a s d e s i g n e d to c o m p a r e t h e clinical and bacteriological efficacy of cefuroxime/ c e f u r o x i m e a x e t i l a n d a m o x i c i l l i n / C A as i n t r a venous followed by oral regimens for the treatment of pneumonia or acute exacerbations of chronic bronchitis or bronchiectasis.
Patients and Methods The study was conducted in 22 hospitals in Belgium, France, Greece, Holland, Israel, New Zealand, Switzerland and Germany, with 18 centres (81.8 %) recruiting ten or more patients per centre. All patients gave their informed consent to participate in the study, which was approved by the ethics committee at each participating centre. In order to detect a 10 % increase or a 12 % decrease in the clinical cure/improvement rate with cefuroxime/ eefuroxime axetil when the expected clinical cure/improvement rate using intravenous followed by oral amoxicillin/CA is 80 %, with 80 % power and using a 5 % level of significance, 200 evaluable patients per treatment group were required. To allow for 15% un.evaluability, a total of 460 patients were needed to enter into the study. Adult male or female hospitalised patients requiring initial intravenous antibiotic therapy for pneumoma or acute exacerbations of chronic bronchitis or bronchiectasis were entered. Pneumonia was defined as an acute lower respiratory tract infection associated with fever and focal signs of infection on examination, confirmed radiographically by new (previously unrecorded) pulmonary infiltrates. Acute infective exacerbations of chronic bronchitis or bronchiectasis were defined as an increase in the symptoms of cough and dyspnoea, along With an increase in the volume and purulence of sputum, in the absence of any new (previously unrecorded) pulmonary infiltrates. Patients excluded were those known to be hypersensitive to penicillins or cephalosporins, those who had received antibiotic therapy during the previous 48 h unless they had clinically failed to respond, those from whom pathogens resistant to the study drugs were isolated prior to entry, and those who were considered terminally ill or Who required assisted ventilation. In addition, patients with bronchial carcinoma, pulmonary tuberculosis, atypical pneumonia (due to legionella or mycoplasma) or left
119
ventricular failure were also excluded, as were pregnant or breast-feeding women. Patients could only be entered once.
The study was conducted non-blindly due to the difficulty of disguising dissimilar formulations. The treatments were randomly allocated to a complete list of patient numbers. Patients were then entered and allocated a patient number in sequential order, Cefuroxime was given as 750 mg by slow intravenous injection or infusion three times daily for 48 to 72 h, followed by eefuroxime axetil tablets 500 mg twice daily for at least five days. Amoxicillin/CA was given similarly as 1.2 g t.i.d, intravenously followed by 625 mg t.i.d, orally. Patients were instructed to take eefuroxime axetil tablets after meals and amoxicillin/CA tablets before meals. Concurrent administration of other antibiotics was not permitted. Before treatment, patients underwent a full clinical examination including chest X-ray. Sputum was obtained, where possible, with the help of a physiotherapist. If produced, it was acceptable for culture only if the Gram stain revealed less than ten epithelial cells and greater than 25 polymorphonuclear leucocytes per low power field. Isolates considered pathogenic were identified and tested for susceptibility to cefuroxime, amoxicillin and amoxicillin/CA by disc diffusion and, where appropriate, for production of beta-lactamase. An interina assessment of the patient's clinical response and the response of clinical signs and symptoms was performed at 48 to 72 h, at the time when treatment was changed from intravenous to oral. The total number of intravenous doses administered was recorded. A full clinical examination was performed after five days of oral treatment. A further sputum sample was collected (wherever possible) and sent for culture and susceptibility testing. The patient's clinical response to treatment was assessed by the investigator and recorded as follows: cure: absence of signs and symptoms of infection at the time treatment was stopped; improvement: clinical signs and symptoms subsided but with incomplete resolution of infection during the treatment period and/or the need for further therapy with the same antibiotic; failure: no response to therapy; and relapse: recurrence of the clinical signs or symptoms of the initial infection during the follow-up period after initial cure or improvement. Bacteriological response was assessed as follows: clearance: absence or reduction to clinically insignificant numbers of the original pathogen(s); failure: persistence of the original pathogen(s) in clinically significant numbers in the post-treatment sample; or relapse: recurrence after initial clearance of the same pathogen(s) within one week of the end of treatment. A follow-up assessment was made seven to 28 days after the end of treatment to check for clinical relapse. At this time a repeat chest X-ray was taken if the pre-treatment X-ray had been abnormal. Clinical and bacteriological efficacy plus relapse rates in the treatment groups were compared separately for bronchitic and pneumonia patients using log-linear models. Similarly, treatment groups were compared with respect to incidence of adverse events using log-linear models.
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Eur. J. Clin. Microbiol. Infect. Dis.
Results
culosis diagnosed in one case after enrollment (one in each treatment group).
Of the 512 patients entered in the study, 241 were diagnosed as having bronchitis or bronchiectasis and 271 with pneumonia; only 23 patients were considered to have nosocomial pneumonia. Approximately 60 % of the patients in each treatment group were smokers or ex-smokers, and about half of them were suffering from concurrent diseases such as bronchial asthma or heart disease. The majority were also receiving additional supportive therapy such as oxygen, oral or intravenous hydration, or steroids. A summary of patient demography is presented in Table 1. The cefuroxime/cefuroxime axetil and amoxicillin/CA groups were similar with respect to age, sex, concurrent diseases, previous antibiotic therapy and presence/absence of cough, dyspnoea and sputum. The numbers of patients considered unevaluable in the two treatment groups were not significantly different. A total of 10 (3.9 %) patients in the cefuroxime/cefuroxime axetil group and 11 (4.3 % ) in the amoxicillin/CA group were unevaluable for the post-treatment assessment of clinical response. Unevaluability was mainly due to major violation of the protocol or withdrawal because of deterioration due to an underlying condition or misdiagnosis, e.g. tuber-
The responses of the principal clinical symptoms cough, sputum production and dyspnoea were compared by calculating the percentage of patients who showed an improvement between their pre- and post-treatment symptom assessments. Cough was graded as absent, infrequent or frequent; sputum as mucoid, mucopurulent, purulent or none produced; and dyspnoea as absent, minimal or moderate (at rest). From 74 to 87 % of patients showed improvement of symptoms, with no difference between treatment groups for any individual assessment. Overall, in an intention-to-treat analysis, 223 of 256 ( 8 7 . 1 % ) patients in the cefuroxime/ cefuroxime axetil group were clinically cured or improved, compared to 220 of 256 (85.9 %) in the amoxicillin/CA group. The clinical responses at the post-treatment assessment for patients with acute exacerbations of chronic bronchitis or chronic bronchiectasis and for patients with pneumonia are shown separately in Table 2. In patients with bronchitis or bronchiectasis, the response to the two regimens was similar, with clinical cure or improvement observed in 89 % of cefuroxime/cefuroxime axetit treated patients
Table 1: Demographic data on patients treated. Cefuroxime/ cefuroxime axetil
Amoxicillin + clavulanic acid
256 168 88
256 179 76 1
18-97 64.3
18-96 62.7
76 79 4
82 71 1
Concurrent disease Cardiovascular disease Congestive cardiac failure Other respiratory diseases Gastrointestinal diseases Diabetes Neurological disorders
134 50 19 32 22 13 12
123 43 14 39 18 13 8
Dyspnoea Moderate At rest Cyanosis Sputum (mucopurulent/purulent)
80 73 67 186
79 67 65 196
No. of patients treated Male Female No data Age range (years) Mean age (years) Smokers Ex-smokers No data
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Table 2: Clinical response post treatment in patients with bronchitis/bronchiectasis and pneumonia.
Clinical
Bronchitis"
response
Pneumonia
Cefuroxime/ cefuroxime axetil
Amoxiciltin/CA
Cefuroxime/ cefuroxime axetil
Amoxicillin/CA
65 (54.6 % ) 41 (34.4 %) 9 (7.6 %) 4 (3.4%)
61 (50,0 %) 51 (41,8 %) 5 (4.1%) 5 (4.1%)
80 (58.4 % ) 37 (27.0 %) 14(10.2 %) 6 (4.4%)
63 (47,0 % ) 45 (33.6 %) 20(14,9 %) 6 (4.5%)
Cured Improved l~ailure Unevaluable Total
119
122
137
134
a Including 13 cefuroxime/cefuroxime axetil- and 14 amoxicillin/CA-treated patients with acute exacerbations of bronchiectasis.
Table 3: Clinical response at follow-up assessment in patients with bronchitis and pneumonia.
Clinical
Pneumonia
Bronchitis"
response
Cefuroxime/ cefuroxime axetil
AmoxicillintCA
Cefuroxime/ cefuroxime axetil
Amoxicillin/CA
80 (75.5 % ) 16 (15.1%) 10 (9.4 %)
81 (72.3 %) 18 (16.1%) 13 (11.6 %)
101 (86.3 % ) 4 (3.4 %) 12(10.3 %)
94 (87.0 % ) 2 (1.9 %) 12(11.1%)
Maintained Cure/improvemen t Relapse Not evaluable Total
106
112
117
108
a
Including patients with acute exacerbations of chronic bronchiectasis. Table 4: Chest X-ray changes in pneumonia patients.
Clinical response Complete resolution Improved Nochange Worse Notdone Total
Cefuroxime/ ccfuroxime axetil
Amoxicillin/CA
49 (36,3 %) 66 (48.9 %) 7 (5.2 %) 6 (4.4 %) 7 (5.2%)
41 (35.0 %) 63 (53.8 %) 6 (5.1%) 1 (0,9 %) 6 (5.1%)
135
and in 91.8 % of amoxicillin/CA-treated patients. In those patients with pneumonia, the cure/imProvement rates were slightly lower, although similar, for both regimens (85.4 % and 80.6 %, respectively). The clinical responses at the follow-up assessment for patients cured or improved at the initial posttreatment assessment are presented in Table 3. Those patients who did not attend the follow-up assessment were considered unevaluable (22 and 25 patients, respectively). The maintained cure plus improvement rates were similar for the two regimens in patients with acute exacerbations of
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bronchitis and bronchiectasis and in patients with pneumonia. Combining the diagnoses, the maintained cure plus improvement rates were similar for the two groups: 181 of 223 (81.2 %) of all patients treated with cefuroxime/cefuroxime axetil and 175 of 220 (79.5 %) of all patients treated with amoxicillin/CA. The same number of patients (n = 20) relapsed in both groups, the majority of relapses occurring in bronchitis patients. Changes in the chest X-ray results between pretreatment and follow-up assessments for those patients with pneumonia are presented in Table 4.
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Eur. J. Clin. Microbiol. Infect. Dis,
Table 5: Bacteriological response for primary pathogens isolated in bronchitits and bronchieetasis patients.
Pathogen Moraxella catarrhalis Haemophilus influenzae Haemophilus parainfluenzae Haemophilus spp. Streptococcus pneumoniae Staphylococcus aureus Klebsiella pneumoniae
Total
Cefuroxime/cefuroximeaxetil
Amoxicillin/CA
Cleared
Total
Cleared
Total
9 15" 1 4b 11 6 0
9 19 5 5 12 6 0
7 16 2 1 11 2 0
7 20 5 3 11 2 3
46 (82.1%)
56
39 (76.4 %)
51
a l relapse, 1 reinfection. bI relapse. Table 6: Bacteriologicalresponse for primarypathogensisolatedin pneumoniapatients. Pathogen Moraxella catarrhalis Haemophilus influenzae Haemophilus parainfluenzae H aemoph ilus spp. Streptococcus pneumoniae Staphylococcus aureus Klebs&lla pneumoniae
Total
Cefuroxime/ce[uroximeaxetil
Amoxicillin/CA
Cleared
Total
Cleared
Total
2 11 0 1 12 3 0
3 12 0 1 12 3 0
5 5 0 0 9 2 1
5 6 0 0 9 4 2
29 (93.5 %)
31
22 (84.6 %)
26
Altogether, 85.2 % (115 of 135) of the cefuroxime/cefuroxime axetil-treated patients had a complete resolution or improvement in the infiltrate observed on the pre-treatment chest X-ray compared to 88.8 % (104 of 117) of the amoxicillin/CA-treated patients. This difference was not significant. A positive pre-treatment sputum sample was obtained in 224 (44 %) patients; 56 of these (25 %) harboured mixed infections. A total of 288 isolates were obtained, of which 164 (57 %) were considered pathogenic. Among evatuable patients with bronchitis or bronchiectasis, a bacteriologic clearance or presumed clearance was achieved for 46 of 56 (82.1%) pathogens isolated in the cefuroxime group and for 39 of 51 (76.4 %) in the amoxicillin/CA group (Table 5). In those patients with pneumonia, bacteriological clearance or presumed clearance was achieved for 29 of 31 (93.5 %) pathogens isolated in the cefuroxime group and for 22 of 26 (84.6 %) in the amoxicillin/CA group (Table 6). The difference in clearance or presumed clearance for both
bronchitic/bronchiectasis and pneumonia patients was not statistically significant between the two antibiotic groups. The most commonly occurring pathogens were Haemophilus infiuenzae, Streptococcus pneumoniae and Moraxella catarrhalis, accounting for 34.8 %, 26.8 % and 14.6 % of the pathogens, respectively. Fourteen beta-lactamase producing pathogens were isolated from the cefuroxime group compared to 16 in the amoxicillin/CA group, and there were similar clearance rates as well (11 of 14, 78.6 %, and 11 of 16, 68.8 %, respectively). Adverse events were reported in 20 of 256 (7.8 %) patients who received cefuroxime/cefuroxime axetil and in 17 of 256 (6.6 %) of those who received amoxicillin/CA. These events were considered to be possibly, probably or almost certainly related to the study drug in 13 of 256 (5 %) patients treated with cefuroxime/cefuroxime axetil and in 11 of 256 (4.3 %) patients treated with amoxicillin/CA. The majority were mild to moderate in severity in both treatment groups. Just under half of the events in each treatment
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.--..-..._
group (cefuroxime/cefuroxime axetil 9 of 20, 45 %; amoxicillin/CA 8 of 17, 47 %) were gastrointestinal disturbances, and all occurred during oral therapy in both groups. During the study ten patients died from intercurrent problems unrelated to the study medication; these were the only adverse events classified as serious.
It is concluded that cefuroxime given intravenously, followed by cefuroxime/cefuroxime axetil orally, represents an important addition to the treatment available for bronchitis and bronchopneumonia in hospitalised patients with other complicating illnesses. Both the cefuroxime/cefuroxime axetil and the amoxicillin/CA regimens were equally effective and well tolerated.
Discussion This study has shown that in hospitalised patients with lower respiratory tract infection complicating other illness, cefuroxime given as intravenous antibiotic therapy followed by oral cefuroxime axetil produces effective results in approximately 90 % of patients. This result is equivalent to that of a similar regimen of amoxicillin/CA, but with the possible advantage of twice daily administration for cefuroxime axetil. More patients also responded within 72 h to intravenous drug in the cefuroxime group. Both drugs produced good clearance of beta-lactamase producing strains of bacteria in this study. These results are similar to those of a study in which intravenous cefuroxime followed by oral Cephalexin was equally effective to amoxicillin/CA in a similar population (9). The cefuroxime regimen used in the present study allows high blood levels to be obtained initially to effect a rapid response in seriously ill patients, with a switch to more convenient oral therapy after two to three days, when the patient can tolerate this and when bacteriological sensitivities are known. Such a change also requires less medical and nursing supervision and may in theory allow earlier discharge from hospital, although this was not addressed in the present study. As well as reducing hospital stay by producing prompt resolution of infection, an effective antibiotic regimen must also minimize relapse rates, as these form an important part of total inpatient time. Cefuroxime and amoxicillin/CA regimens Were associated with identical and low relapse rates (10 %). Tolerability to such important drugs forms the other part of their overall acceptability to patient and clinician. Both cefuroxime/cefuroxime axetil and amoxicillin/CA were associated With very low adverse event rates of 4 to 5 %. AdVerse events were of only mild to moderate Severity; no serious adverse events attributable to either drug were encountered.
Acknowledgements Our acknowledgements to the other principal investigators in this study: Dr. M.C. Bins, The Netherlands; Dr. Bolcskei, Germany; Dr. E Bonnal, France; Dr. B. Bouros, Greece; Prof. Fabel, Germany; Dr. J. Hogenauer, Germany; Dr. Y,S. Igra, Israel; Prof. R. Keller, Switzerland; Dr. S. Lang, New Zealand; Dr. Olschock, Germany; Dr. D. Ommeslag, Belgium; Dr. H. Pagee, The Netherlands; Dr. Pickl-Pfeffcr, Germany; Dr. C. Seignalet, France; Dr. Stcppling, Germany; Dr. W. Tcnbieg, Germany; Dr. D. Vallee, Germany; Prof. V. van der Straeten, Belgium; Dr. G. Vandermoten, Belgium; Dr. A. Vergnenegre, France. This study was supported by a grant from Glaxo Group Research, UK.
References 1. Smith BR, Le Frock JL: Cefuroxime: antimicrobial activity, pharmacology and clinical efficacy. Therapeutic Drug Monitoring 1983, 5: 149-160. 2. Jones RN, Thornsberry C: In vitro antimicrobial activity, physical characteristics and other microbiological features of cefuroximc: a new study and review. In: Moellcring RC (cd): The clinical significance of the newer bcta-lactam antibiotics-focus on cefuroxime. ADIS Press, New York, 1983, p. 30--45. 3. Gold B, Rodriguez WJ: Cefuroxime: mechanisms of actions, antimicrobial activity,pharmacokinetics, clinical applications, adverse reactions, and therapeutic indications. Pharmacotherapy 1983, 3: 82-100. 4. Harding SM, Williams PEO, Ayrtnn J: Pharmacology of cefuroxime as the 1-acetoxyethylester in volunteers. Antimicrobial Agents and Chemotherapy 1984,25: 7882. 5. Williams PEO, Itarding SM: The absolute bioavariability of oral cefuroxime axetil in male and female volunteers after fasting and after food. Journal of Antimicrobial Chemotherapy 1984, 13: 191-196. 6. De Sommers K, Van Wyk M, Williams PEO, Harding SM: Pharmacokinetics and tolerance of cefuroxime axetil in volunteers during repeated dosing. Antimicrobial Agents and Chemotherapy 1984, 25: 344347.
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7. Wise R, Bennett SA, Dent J: The pharmacokinetics of orally absorbed cefuroxime compared with amoxycillin/clavulanic acid. Journal of Antimicrobial Chemotherapy 1984, 13: 603-610. 8. Waistad RA, Vilsvik JS, Thurmann-Nielsen E, Griggs JV, Brown GW: Pharmacokinetics of cefuroxime axetil in patients with lower respiratory tract infections. A profile of cefuroxime axetil. Practitioner 1988, Supplement: 65-67.
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9. O'Donovan C, Rudd R, O'Neill S, Fitzgerald MX, McNicholas W, FlavelI-Matts SG, Howell F, McKenzie A, Whittaker J: Augmentin (intravenous then oral) compared with cefuroxime followed by cephalexin for chest infections in hospitalised patients. British Journal of Clinical Practice 1987, 41: 1044-1052.
Article
Vol. 11. No. 2
Eur. J. Clin. Microbiol. Infect. Dis., February 1992, p. 118-124 0934-9723/92/02 0118-07 $ 3.00/0
Cefuroxime and Cefuroxime Axetil versus Amoxicillin plus Clavulanic Acid in the Treatment of Lower Respiratory Tract Infections
C. Brambilla 1, S. Kastanakis 2, S. Knight 3, K. Cunningham 3.
In a large multinational study, the clinical and bacteriological efficacy of intravenous cefuroxime 750 mg t.i.d, followed by oral cefuroxime axeti1500 mg b.i.d, was compared to that of amoxiciilin plus clavulanic acid (CA) administered as 1.2 g intravenously t.i.d, followed by 625 mg orally t.i.d, in the treatment of lower respiratory tract infections in hospitalised patients. A total of 512 patients were entered (256 in each treatment group). All were suffering from pneumonia or acute exacerbations of chronic bronchitis or bronchiectasis and required initial parenterai antibiotic therapy. Parenteral therapy lasted 48 to 72 h and was followed by five days of oral therapy. The clinical responses in the two treatment groups were very similar:. 223 of 256 (87.1%) patients were cured or improved with cefuroximelcefuroxime axetU compared to 220 of 256 (85.9 %) with amoxicillin/CA. Positive pre-treatment sputum samples were obtained from 44 % of the patients. Clearance rates obtained were again similar:. 72.8 % with cefuroxime/cefuroxime axetii and 70 % with amoxicillin/CA. Ten percent of the isolates were beta-lactamase producers, similar numbers of which were cleared in both groups. Both regimens were generally well tolerated, with only 5 % of patients treated with the cefuroxime regimen and 4.3 % of patients treated with amoxicillin/CA experiencing drug-related adverse events. Cefuroxime/cefuroxime axetU "follow-on" therapy produces clinical and bacteriological efficacy equivalent to that of amoxiciilin/CA, with the advantage of twice daily oral administration.
Lower respiratory tract infection is a common cause of morbidity, particularly during the winter months. Some patients require admission to hospital, where treatment is generally initiated with a parenterally administered antibiotic. Converting the treatment of such patients to an orally absorbed formulation of the same compound offers the potential of early discharge from hospital. This is a major benefit to the patient and may result in overall savings in the cost of treating such patients. Cefuroxime is an injectable cephalosporin antibiotic with a broad spectrum of antibacterial activity and a high degree of stability against betalactamases produced by gram-negative organisms and staphylococci (1-3). It has been found to be 1Centre Hospitalier Regional et Universitaire, Grenoble, France. 2General Hospital, Chania, Crete, Greece. 3Glaxo Group Research, Greenford Road, Greenford, UK.
effective in a wide range of infectious conditions, including lower respiratory tract infections. Oral cefuroxime sodium is only minimally absorbed and therefore until recently has been limited to intravenous use in hospitalised patients. Cefuroxime axetil is a prodrug of cefuroxime which has been developed for oral administration. It is rapidly hydrolysed in the intestinal mucosa, liberating cefuroxime which is absorbed into the blood. Bioavailability studies indicate that 50 to 60 % of the administered dose of cefuroxime axetil is absorbed when administered after a meal (4, 5; A.B. Straughn et al., 24th ICAAC, 1984, Abstract 592). A 500 mg dose yields peak serum cefuroxime concentrations of 7-10 mg/1 after two to three hours (5-7). It has been shown to penetrate rapidly into sputum and bronchial tissue, producing levels that exceed the MICs for pathogens most frequently associated with lower respiratory tract infections (8; R. Wise et al., 4th European Congress of Clinical Microbiology, 1989, Abstract 762). Cefuroxime has
Vol. 11, 1992
g o o d in v i t r o a c t i v i t y a g a i n s t t h e m a j o r r e s p i r a t o r y p a t h o g e n s such as Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis, KlebsieUa pneumoniae a n d Staphylococcus aureus. The combination of amoxicillin and the beta-lact a m a s e i n h i b i t o r c l a v u l a n i c a c i d ( C A ) is also active a g a i n s t s t r a i n s r e s i s t a n t to p e n i c i l l i n a n d is a v a i l a b l e b o t h as a n i n t r a v e n o u s a n d o r a l formulation. This s t u d y w a s d e s i g n e d to c o m p a r e t h e clinical and bacteriological efficacy of cefuroxime/ c e f u r o x i m e a x e t i l a n d a m o x i c i l l i n / C A as i n t r a venous followed by oral regimens for the treatment of pneumonia or acute exacerbations of chronic bronchitis or bronchiectasis.
Patients and Methods The study was conducted in 22 hospitals in Belgium, France, Greece, Holland, Israel, New Zealand, Switzerland and Germany, with 18 centres (81.8 %) recruiting ten or more patients per centre. All patients gave their informed consent to participate in the study, which was approved by the ethics committee at each participating centre. In order to detect a 10 % increase or a 12 % decrease in the clinical cure/improvement rate with cefuroxime/ eefuroxime axetil when the expected clinical cure/improvement rate using intravenous followed by oral amoxicillin/CA is 80 %, with 80 % power and using a 5 % level of significance, 200 evaluable patients per treatment group were required. To allow for 15% un.evaluability, a total of 460 patients were needed to enter into the study. Adult male or female hospitalised patients requiring initial intravenous antibiotic therapy for pneumoma or acute exacerbations of chronic bronchitis or bronchiectasis were entered. Pneumonia was defined as an acute lower respiratory tract infection associated with fever and focal signs of infection on examination, confirmed radiographically by new (previously unrecorded) pulmonary infiltrates. Acute infective exacerbations of chronic bronchitis or bronchiectasis were defined as an increase in the symptoms of cough and dyspnoea, along With an increase in the volume and purulence of sputum, in the absence of any new (previously unrecorded) pulmonary infiltrates. Patients excluded were those known to be hypersensitive to penicillins or cephalosporins, those who had received antibiotic therapy during the previous 48 h unless they had clinically failed to respond, those from whom pathogens resistant to the study drugs were isolated prior to entry, and those who were considered terminally ill or Who required assisted ventilation. In addition, patients with bronchial carcinoma, pulmonary tuberculosis, atypical pneumonia (due to legionella or mycoplasma) or left
119
ventricular failure were also excluded, as were pregnant or breast-feeding women. Patients could only be entered once.
The study was conducted non-blindly due to the difficulty of disguising dissimilar formulations. The treatments were randomly allocated to a complete list of patient numbers. Patients were then entered and allocated a patient number in sequential order, Cefuroxime was given as 750 mg by slow intravenous injection or infusion three times daily for 48 to 72 h, followed by eefuroxime axetil tablets 500 mg twice daily for at least five days. Amoxicillin/CA was given similarly as 1.2 g t.i.d, intravenously followed by 625 mg t.i.d, orally. Patients were instructed to take eefuroxime axetil tablets after meals and amoxicillin/CA tablets before meals. Concurrent administration of other antibiotics was not permitted. Before treatment, patients underwent a full clinical examination including chest X-ray. Sputum was obtained, where possible, with the help of a physiotherapist. If produced, it was acceptable for culture only if the Gram stain revealed less than ten epithelial cells and greater than 25 polymorphonuclear leucocytes per low power field. Isolates considered pathogenic were identified and tested for susceptibility to cefuroxime, amoxicillin and amoxicillin/CA by disc diffusion and, where appropriate, for production of beta-lactamase. An interina assessment of the patient's clinical response and the response of clinical signs and symptoms was performed at 48 to 72 h, at the time when treatment was changed from intravenous to oral. The total number of intravenous doses administered was recorded. A full clinical examination was performed after five days of oral treatment. A further sputum sample was collected (wherever possible) and sent for culture and susceptibility testing. The patient's clinical response to treatment was assessed by the investigator and recorded as follows: cure: absence of signs and symptoms of infection at the time treatment was stopped; improvement: clinical signs and symptoms subsided but with incomplete resolution of infection during the treatment period and/or the need for further therapy with the same antibiotic; failure: no response to therapy; and relapse: recurrence of the clinical signs or symptoms of the initial infection during the follow-up period after initial cure or improvement. Bacteriological response was assessed as follows: clearance: absence or reduction to clinically insignificant numbers of the original pathogen(s); failure: persistence of the original pathogen(s) in clinically significant numbers in the post-treatment sample; or relapse: recurrence after initial clearance of the same pathogen(s) within one week of the end of treatment. A follow-up assessment was made seven to 28 days after the end of treatment to check for clinical relapse. At this time a repeat chest X-ray was taken if the pre-treatment X-ray had been abnormal. Clinical and bacteriological efficacy plus relapse rates in the treatment groups were compared separately for bronchitic and pneumonia patients using log-linear models. Similarly, treatment groups were compared with respect to incidence of adverse events using log-linear models.
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Eur. J. Clin. Microbiol. Infect. Dis.
Results
culosis diagnosed in one case after enrollment (one in each treatment group).
Of the 512 patients entered in the study, 241 were diagnosed as having bronchitis or bronchiectasis and 271 with pneumonia; only 23 patients were considered to have nosocomial pneumonia. Approximately 60 % of the patients in each treatment group were smokers or ex-smokers, and about half of them were suffering from concurrent diseases such as bronchial asthma or heart disease. The majority were also receiving additional supportive therapy such as oxygen, oral or intravenous hydration, or steroids. A summary of patient demography is presented in Table 1. The cefuroxime/cefuroxime axetil and amoxicillin/CA groups were similar with respect to age, sex, concurrent diseases, previous antibiotic therapy and presence/absence of cough, dyspnoea and sputum. The numbers of patients considered unevaluable in the two treatment groups were not significantly different. A total of 10 (3.9 %) patients in the cefuroxime/cefuroxime axetil group and 11 (4.3 % ) in the amoxicillin/CA group were unevaluable for the post-treatment assessment of clinical response. Unevaluability was mainly due to major violation of the protocol or withdrawal because of deterioration due to an underlying condition or misdiagnosis, e.g. tuber-
The responses of the principal clinical symptoms cough, sputum production and dyspnoea were compared by calculating the percentage of patients who showed an improvement between their pre- and post-treatment symptom assessments. Cough was graded as absent, infrequent or frequent; sputum as mucoid, mucopurulent, purulent or none produced; and dyspnoea as absent, minimal or moderate (at rest). From 74 to 87 % of patients showed improvement of symptoms, with no difference between treatment groups for any individual assessment. Overall, in an intention-to-treat analysis, 223 of 256 ( 8 7 . 1 % ) patients in the cefuroxime/ cefuroxime axetil group were clinically cured or improved, compared to 220 of 256 (85.9 %) in the amoxicillin/CA group. The clinical responses at the post-treatment assessment for patients with acute exacerbations of chronic bronchitis or chronic bronchiectasis and for patients with pneumonia are shown separately in Table 2. In patients with bronchitis or bronchiectasis, the response to the two regimens was similar, with clinical cure or improvement observed in 89 % of cefuroxime/cefuroxime axetit treated patients
Table 1: Demographic data on patients treated. Cefuroxime/ cefuroxime axetil
Amoxicillin + clavulanic acid
256 168 88
256 179 76 1
18-97 64.3
18-96 62.7
76 79 4
82 71 1
Concurrent disease Cardiovascular disease Congestive cardiac failure Other respiratory diseases Gastrointestinal diseases Diabetes Neurological disorders
134 50 19 32 22 13 12
123 43 14 39 18 13 8
Dyspnoea Moderate At rest Cyanosis Sputum (mucopurulent/purulent)
80 73 67 186
79 67 65 196
No. of patients treated Male Female No data Age range (years) Mean age (years) Smokers Ex-smokers No data
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Table 2: Clinical response post treatment in patients with bronchitis/bronchiectasis and pneumonia.
Clinical
Bronchitis"
response
Pneumonia
Cefuroxime/ cefuroxime axetil
Amoxiciltin/CA
Cefuroxime/ cefuroxime axetil
Amoxicillin/CA
65 (54.6 % ) 41 (34.4 %) 9 (7.6 %) 4 (3.4%)
61 (50,0 %) 51 (41,8 %) 5 (4.1%) 5 (4.1%)
80 (58.4 % ) 37 (27.0 %) 14(10.2 %) 6 (4.4%)
63 (47,0 % ) 45 (33.6 %) 20(14,9 %) 6 (4.5%)
Cured Improved l~ailure Unevaluable Total
119
122
137
134
a Including 13 cefuroxime/cefuroxime axetil- and 14 amoxicillin/CA-treated patients with acute exacerbations of bronchiectasis.
Table 3: Clinical response at follow-up assessment in patients with bronchitis and pneumonia.
Clinical
Pneumonia
Bronchitis"
response
Cefuroxime/ cefuroxime axetil
AmoxicillintCA
Cefuroxime/ cefuroxime axetil
Amoxicillin/CA
80 (75.5 % ) 16 (15.1%) 10 (9.4 %)
81 (72.3 %) 18 (16.1%) 13 (11.6 %)
101 (86.3 % ) 4 (3.4 %) 12(10.3 %)
94 (87.0 % ) 2 (1.9 %) 12(11.1%)
Maintained Cure/improvemen t Relapse Not evaluable Total
106
112
117
108
a
Including patients with acute exacerbations of chronic bronchiectasis. Table 4: Chest X-ray changes in pneumonia patients.
Clinical response Complete resolution Improved Nochange Worse Notdone Total
Cefuroxime/ ccfuroxime axetil
Amoxicillin/CA
49 (36,3 %) 66 (48.9 %) 7 (5.2 %) 6 (4.4 %) 7 (5.2%)
41 (35.0 %) 63 (53.8 %) 6 (5.1%) 1 (0,9 %) 6 (5.1%)
135
and in 91.8 % of amoxicillin/CA-treated patients. In those patients with pneumonia, the cure/imProvement rates were slightly lower, although similar, for both regimens (85.4 % and 80.6 %, respectively). The clinical responses at the follow-up assessment for patients cured or improved at the initial posttreatment assessment are presented in Table 3. Those patients who did not attend the follow-up assessment were considered unevaluable (22 and 25 patients, respectively). The maintained cure plus improvement rates were similar for the two regimens in patients with acute exacerbations of
117
bronchitis and bronchiectasis and in patients with pneumonia. Combining the diagnoses, the maintained cure plus improvement rates were similar for the two groups: 181 of 223 (81.2 %) of all patients treated with cefuroxime/cefuroxime axetil and 175 of 220 (79.5 %) of all patients treated with amoxicillin/CA. The same number of patients (n = 20) relapsed in both groups, the majority of relapses occurring in bronchitis patients. Changes in the chest X-ray results between pretreatment and follow-up assessments for those patients with pneumonia are presented in Table 4.
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Eur. J. Clin. Microbiol. Infect. Dis,
Table 5: Bacteriological response for primary pathogens isolated in bronchitits and bronchieetasis patients.
Pathogen Moraxella catarrhalis Haemophilus influenzae Haemophilus parainfluenzae Haemophilus spp. Streptococcus pneumoniae Staphylococcus aureus Klebsiella pneumoniae
Total
Cefuroxime/cefuroximeaxetil
Amoxicillin/CA
Cleared
Total
Cleared
Total
9 15" 1 4b 11 6 0
9 19 5 5 12 6 0
7 16 2 1 11 2 0
7 20 5 3 11 2 3
46 (82.1%)
56
39 (76.4 %)
51
a l relapse, 1 reinfection. bI relapse. Table 6: Bacteriologicalresponse for primarypathogensisolatedin pneumoniapatients. Pathogen Moraxella catarrhalis Haemophilus influenzae Haemophilus parainfluenzae H aemoph ilus spp. Streptococcus pneumoniae Staphylococcus aureus Klebs&lla pneumoniae
Total
Cefuroxime/ce[uroximeaxetil
Amoxicillin/CA
Cleared
Total
Cleared
Total
2 11 0 1 12 3 0
3 12 0 1 12 3 0
5 5 0 0 9 2 1
5 6 0 0 9 4 2
29 (93.5 %)
31
22 (84.6 %)
26
Altogether, 85.2 % (115 of 135) of the cefuroxime/cefuroxime axetil-treated patients had a complete resolution or improvement in the infiltrate observed on the pre-treatment chest X-ray compared to 88.8 % (104 of 117) of the amoxicillin/CA-treated patients. This difference was not significant. A positive pre-treatment sputum sample was obtained in 224 (44 %) patients; 56 of these (25 %) harboured mixed infections. A total of 288 isolates were obtained, of which 164 (57 %) were considered pathogenic. Among evatuable patients with bronchitis or bronchiectasis, a bacteriologic clearance or presumed clearance was achieved for 46 of 56 (82.1%) pathogens isolated in the cefuroxime group and for 39 of 51 (76.4 %) in the amoxicillin/CA group (Table 5). In those patients with pneumonia, bacteriological clearance or presumed clearance was achieved for 29 of 31 (93.5 %) pathogens isolated in the cefuroxime group and for 22 of 26 (84.6 %) in the amoxicillin/CA group (Table 6). The difference in clearance or presumed clearance for both
bronchitic/bronchiectasis and pneumonia patients was not statistically significant between the two antibiotic groups. The most commonly occurring pathogens were Haemophilus infiuenzae, Streptococcus pneumoniae and Moraxella catarrhalis, accounting for 34.8 %, 26.8 % and 14.6 % of the pathogens, respectively. Fourteen beta-lactamase producing pathogens were isolated from the cefuroxime group compared to 16 in the amoxicillin/CA group, and there were similar clearance rates as well (11 of 14, 78.6 %, and 11 of 16, 68.8 %, respectively). Adverse events were reported in 20 of 256 (7.8 %) patients who received cefuroxime/cefuroxime axetil and in 17 of 256 (6.6 %) of those who received amoxicillin/CA. These events were considered to be possibly, probably or almost certainly related to the study drug in 13 of 256 (5 %) patients treated with cefuroxime/cefuroxime axetil and in 11 of 256 (4.3 %) patients treated with amoxicillin/CA. The majority were mild to moderate in severity in both treatment groups. Just under half of the events in each treatment
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.--..-..._
group (cefuroxime/cefuroxime axetil 9 of 20, 45 %; amoxicillin/CA 8 of 17, 47 %) were gastrointestinal disturbances, and all occurred during oral therapy in both groups. During the study ten patients died from intercurrent problems unrelated to the study medication; these were the only adverse events classified as serious.
It is concluded that cefuroxime given intravenously, followed by cefuroxime/cefuroxime axetil orally, represents an important addition to the treatment available for bronchitis and bronchopneumonia in hospitalised patients with other complicating illnesses. Both the cefuroxime/cefuroxime axetil and the amoxicillin/CA regimens were equally effective and well tolerated.
Discussion This study has shown that in hospitalised patients with lower respiratory tract infection complicating other illness, cefuroxime given as intravenous antibiotic therapy followed by oral cefuroxime axetil produces effective results in approximately 90 % of patients. This result is equivalent to that of a similar regimen of amoxicillin/CA, but with the possible advantage of twice daily administration for cefuroxime axetil. More patients also responded within 72 h to intravenous drug in the cefuroxime group. Both drugs produced good clearance of beta-lactamase producing strains of bacteria in this study. These results are similar to those of a study in which intravenous cefuroxime followed by oral Cephalexin was equally effective to amoxicillin/CA in a similar population (9). The cefuroxime regimen used in the present study allows high blood levels to be obtained initially to effect a rapid response in seriously ill patients, with a switch to more convenient oral therapy after two to three days, when the patient can tolerate this and when bacteriological sensitivities are known. Such a change also requires less medical and nursing supervision and may in theory allow earlier discharge from hospital, although this was not addressed in the present study. As well as reducing hospital stay by producing prompt resolution of infection, an effective antibiotic regimen must also minimize relapse rates, as these form an important part of total inpatient time. Cefuroxime and amoxicillin/CA regimens Were associated with identical and low relapse rates (10 %). Tolerability to such important drugs forms the other part of their overall acceptability to patient and clinician. Both cefuroxime/cefuroxime axetil and amoxicillin/CA were associated With very low adverse event rates of 4 to 5 %. AdVerse events were of only mild to moderate Severity; no serious adverse events attributable to either drug were encountered.
Acknowledgements Our acknowledgements to the other principal investigators in this study: Dr. M.C. Bins, The Netherlands; Dr. Bolcskei, Germany; Dr. E Bonnal, France; Dr. B. Bouros, Greece; Prof. Fabel, Germany; Dr. J. Hogenauer, Germany; Dr. Y,S. Igra, Israel; Prof. R. Keller, Switzerland; Dr. S. Lang, New Zealand; Dr. Olschock, Germany; Dr. D. Ommeslag, Belgium; Dr. H. Pagee, The Netherlands; Dr. Pickl-Pfeffcr, Germany; Dr. C. Seignalet, France; Dr. Stcppling, Germany; Dr. W. Tcnbieg, Germany; Dr. D. Vallee, Germany; Prof. V. van der Straeten, Belgium; Dr. G. Vandermoten, Belgium; Dr. A. Vergnenegre, France. This study was supported by a grant from Glaxo Group Research, UK.
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