Current Medical Research and Opinion
Vol. 5, No. 10, 1979
-
Cefuroxime in the treatment of lower respiratory tract infection
R. P. Bax,* M.B., B.S., M.R.C.S.,L.R.C.P.,
A. F. Dawson, M.B., Ch.B., Brenda M. Mullinger, B.Sc., and
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C. H. Dash, M.B., Ch.B.,Dip. Pharm.Med., D.Obst.R.C.0.G. Glaxo-Allenbarys Research (Greenford) Ltd., Glaxo Holdings Ltd., London, and Medical Dept., Glaxo Laboratories Ltd., Greenfbrd, England
Curr. Med. Res. Opin., (1979), 5,772.
Received: 20th November 1978
Summary Cefuroxime is ci new parenteral antibiotic with a wider spectrum of activity than earlier cephulosporins arid is particulurly active against Haemophilus influenme, including strains resistant to ampicillin due to j3-lactamuse production. From 18 centres, 274 patients suflering with 275 ir$ections were treated with cefuroxime sodium using the standard regimen of 750 rng 8-hourly by intramuscular injection. The clinical results showed a 90% success rate in the putients with bronchopneumonia (105), 91 % in patients with post-operative pneumonia (74), and 89% in the patients with acute exacerbations of chronic bronchitis (96). Renal function was closely monitored during therupy, and no adverse changes attributable to cefuroxime therapy were seen in any patient, including those M-ho also received frusemide. Two patients (0.7 %) developed a rash, although 8 penicillin-allergic patients were treated without incident, From these studies, it can be concluded that 750 mng refuroxirne 8-hourly is effective in the treatment of lotver respiratory tract infections. It is suggested that the attributes of this antibiotic may offer several advantages over existing therapies. Key Mgords: Cefuroxime - cephalosporins - respiratory tract infections
Introduction Severe lower respiratory tract infection is one of the commonest reasons for hospital admission in the United Kingdom. Bacteriology of sputum is not a reliable method of identifying the pathogen for many reasons ;9 for example, the infection occurs deep in the respiratory tract, and expectorated sputum is often contaminated by commensal organisms. In addition, many patients admitted to hospital with such infections will have already been treated unsuccessfully with a course of oral antibiotics which causes difficulty in interpreting sputum bacteriology. Invasive diagnostic techniques are not justified for the majority of patients but the organisms commonly responsible for lower respiratory tract infections are well known. An ideal antibiotic would be highly active against all these pathogens, particularly those ~~
*Present address: Roussel Laboratories Ltd., Wembley Park, Middlesex, England 172
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R. P. Bax, A, F. Dawson, Brenda M. Mullinger and C . H. Dash
which have become resistant to the commonly prescribed oral antibiotics such as ampicillin and tetracyclines. Such an antibiotic should reliably produce high serum and sputum levels, should be well tolerated by the patient, and be safe to usein everyday clinical practice. Cefuroxime sodium, a new semi-synthetic parenteral cephalosporin antibiotic, appears to have such properties,’ . 1 o,l and encouraging clinical results have been reported from initial clinical studies, although a variety of dosage regimens were used in the early dose-ranging investigations.A comparison of 1 g and 750 mg given 8-hourly showed that the clinical results achieved were similar.’ ~1 Subsequently, emphasis was given to treating lower respiratory tract infections with 750 mg 8-hourly by intramuscular injection and this report summarizes the results.
Patients and methods Two hundred and seventy-four patients (183 male, 91 female) suffering from lower respiratory tract infections have been studied, of whom 230 were treated in nine centres in the United Kingdom and 44 were treated in nine centres overseas. The mean age of the patients was 66 years (range 12 to 92 years). The diagnosis was based on the clinical history and generally accepted physiological and radiological signs. There were 105 patients diagnosed as suffering from bronchopneumonia, 74 with post-operative pneumonia proven radiologically, and 95 with acute exacerbations of chronic bronchitis (including 1 patient who was treated on two occasions). Ninety-three patients (34 %) had previously been given antibiotics for their current infection but these had proved unsuccessful. Patients were treated with 750 mg cefuroxine 8-hourly by intramuscular injection. The duration of therapy was determined by the clinician depending on the individual patient’s response to treatment. Details of history, symptoms and signs, previous antibiotic therapy, concomitant drug therapy, response to treatment, side-effects, if any, and the acceptability of cefuroxime injection were recorded on a standard 10-pageclinical trial record form which ensured uniformity of the data collected. Chest X-rays, bacteriology of sputum, urinalysis and haematological and biochemical tests were performed before and after cefuroxime and, if possible, during treatment. The clinical response to treatment was assessed by the clinician as ‘excellent’ when there was complete remission of symptoms and signs; ‘improved’, a good, adequate clinical response but short of complete remission within the treatment period; and ‘failed’when there was no improvement or worsening. The tolerance of the intramuscular injections was assessed by means of a scoring system for intensity, duration and frequency of pain.
Results Duration of treatment The duration of the treatment was 5 to 8 days for 190 patients, and 9 to 11 days for a further 78. Thus, most of the patients required treatment for 8 days or less. Bacteriological findings Specimens for bacteriological examination were not always obtained from patients 773
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Cefuroximein the treatment of lower respiratory tract infection
before and after treatment, because many patients who had an excellent response to cefuroxime did not produce sputum at the end of therapy and, therefore, were unassessable bacteriologically. However, sputum bacteriology was performed before and after treatment in 128 patients, but in 36 no pathogens were isolated on either occasion. Of the remaining 92 patients (Table I), 72 had their initial organisms eradicated, but in 10 of these Candida albicans was isolated from their post-treatment specimen. Fourteen patients were classified as bacteriological failures because the pathogens present in the pre-treatment samples persisted throughout treatment. Patients classified bacteriologically as ‘partial success’ included those whose initial sputum contained a variety of organisms, some of which persisted at the end of treatment. In only 3 cases were organisms resistant to cefuroxime; Pseudomonas aeruginosa was cultured from the sputum of 2 patients and Serratia marcescens from the third. One of the Ps. aeruginosa and the S. marcescens disappeared from the sputum during the treatment period. Table I. Bacteriological response in 92 patients Diagnosis
Eradicated
Partial success
Bronchopneumonia Post-operative pneumonia Acute exacerbation of bronchitis
35 19 18
2 3 1
5
Total
72
6
14
Persisted
2 7
Ten patients classified as bacteriological failures were judged to have been clinical successes, whereas 6 patients who failed clinically were bacteriological successes (Table 11).Although there seems to be a positive relationship between clinical success and eradication of bacteria, the differences did not reach statistical significance at the 5 % level. Table II. Clinical and bacteriologicalresponse: the percentages are related to the totals shown Clinical results
Bacteriological response Eradicated
Partial success
Persisted
Success Failure
66 (92%) 6 (8%)
5 (83%)
10(71%) 4 (29%)
Total
72
6
1(17%)
Clinicalfindings Amongst the 214 patients there were only 23 patients who were categorized as ‘failed’ at the end of treatment, but an additional 5 relapsed within 7 days of stopping treatment and these have been classified similarly. These 28 patients occurred proportionately in the three diagnostic groups (Table 111). Three patients died during the cefuroximetherapy: 1 of a post-operative aspiration pneumonia and 2 of cerebrovascular accidents. In none of these 3 patients had 774
R. P. Bax, A. F. Dawson, Brenda M. Mullinger and C. H. Dash
Table 111. Clinical response in 275 infections in 274 patients
Diagnosis
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Improved
Failed
Bronchopneumonia Post-operative pneumonia Acute exacerbation of bronchitis
Excellent 65
30
10
45 55
22 30
7 11
Total
165
82
28
there been any improvement of their presenting infection. Over 90 % of those with bronchopneumonia OT post-operative pneumonia responded satisfactorily, as did almost 90% of those with acute exacerbations of chronic bronchitis. Fourteen of the 28 failures had pre-existing diseases, such as severe cardiovascular disease or chronic obstructive airways disease. Clinicians were asked to record the day of relief of symptoms. The majority of patients (84 %) experienced relief of all symptoms by the end of the fourth day of treatment (Figure 1). Figure 1. Day of relief of presenting symptoms
60
20
k
1 2 3
L
Side-e__flects Data on the local discomfort from the injections of cefuroxime sodium were available from 245 patients. Amongst these, 130 (53.1 %) stated that the injections were not painful, 83 (33.9 %) experienced mild pain, 28 (I 1.4%) experienced moderate pain, and only 4 (1.6 %) of the patients experienced severe pain. Thus, 115 patients (47 %) found the injections produced discomfort but only 29 (12 %) found the pain lasted for more than 3 minutes and 4 (1.6 %) for more than 10 minutes. Other side-effects were rare and only occurred in 6 patients. There were two incidents of diarrhoea, both in the patient who had received cefuroxime on two occasions. The second treatment was stopped because of the severityof the diarrhoea. In 2 other patients there were reports of faintness and sweating, but these were probably not related to cefuroxime therapy. Two (0.7 %) further patients developed a rash during cefuroxime therapy and the antibiotic was stopped in one of them. Neither was allergic to penicillin. Eight patients with a history of penicillin-allergy were treated without incident. 775
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Cefuroxirne in the treatment of lower respiratory tract infection
Laboratory Jindings There was no patient who had a clinical episode of acute oliguria or of renal failure due to cefuroxime therapy. Serial estimations of plasma urea and creatinine were carried out in 166 patients before and after treatment. Seventeen patients had received frusemide concurrently. Not uncommonly, the levels of urea and creatinine before and after treatment were different and it is highly likely that these fluctuations represent common random biochemical changes of a minor degree. In order to monitor closely renal tolerance of cefuroxime, the clinical records were carefully scrutinized for all patients whose plasma urea or creatinine concentrations either became abnormal after initially being normal or, if already abnormal, increased further. There were 41 patients in these categories, but in 27 the changes were ascribed to underlying disease by the attendant clinician. Of the remaining 14 patients, 3 patients had an increase in urea of about 1.5mmol/l, 4 of about 2.5 mmol/l, and 1 of 7 mmol/l. Plasma creatinine increased by 20 ymol/l in 3 patients, by 40 :Amol/l in 2, and by 55 pmol/l in another. Significantly, in no patient was there an increase in both urea and creatinine and it is not likely that these changes signify impairment of renal function. Moreover, there was a number of patients with abnormally high levels of plasma creatinine or urea before treatment and in many of these the values were normal at the end. For plasma urea this occurred in 12 of 29 patients, and for creatinine in 3 of 6. Hence, it is concluded that there were no adverse changes in renal function due to treatment with cefuroxime.
Discussion and Conclusions The patients were selected by the clinicians as those whose condition merited intramuscular antibiotics. The overall results are very encouraging. Only about 10 % of the patients did not respond satisfactorily and there are several possible reasons. A large proportion of these had complicating chronic cardiopulmonary disease which may have been a factor in the lack of response. However, other patients with apparently similar complications responded satisfactorily. It is possible that the infections which did not respond were more severe and should have been treated with a larger dose of cefuroxime, e.g. 1.5 g intravenouslyevery 8 hours. The causative bacteria may have been resistant to cefuroxime but, of the bacteria isolated in this study, only 3 were found to be resistant, and 2 ofthese disappeared during cefuroxime treatment. In previous in vitro studies, very few bacteria liable to infect the lower respiratory tract have been resistant.’ Cefuroxime is consistently and highly active against Haemophilus injuenzae, even those strains resistant to ampicillin through production of P-lactamase. This enzyme hydrolyses the P-lactam bond of ampicillin destroying its antibacterial activity. Although some other cephalosporins have a degree of resistance to this enzyme, they are less resistant than cefuroxime, cannot penetrate the bacterial cell wall so rapidly and, consequently, are not effective. A range of similar enzymes are produced by other Gram-negativebacteria which can infect the lower respiratory tract, such as Klebsiella pneumoniae and Escherichia coli. Cefuroxime is active against these bacteria, largely because of marked stability to 776
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R . P. Bax, A. F. Dawson, Brenda M. Mullinger and C. H . Dash
their p-lactamases,7.8 easy penetrability of the outer cell wall, and specificity for the transpeptidases crucial for cell viability.6 Similarly, cefuroxime is stable to the :J-lactamase (penicillinase) produced by staphylococci.3 Bacteria such as Streptococcus pneumoniue and Streptococcus pyogenes, which are sensitive to a wide range of antibiotics, are sensitive to cefuroxime. A small number of patients in this study, although improved at the end of treatment, relapsed with a few days. These patients were included in the clinical failures. The relapses in chronic bronchitics have been associated with the concentration of antibiotics in the sputum, particularly with ampicillin and amo~ycillin.~.5 It has been shown that within 1 hour of the first intramuscular dose of cefuroxime, a mean concentration of 0.8 pg/g of expectorated sputum can be expected13 which is above the minimum inhibitory concentration (MIC) for 80% of strains of H . infuenzue, and above the MIC for all Str. pneumoniue and Str. pyogenes. The concentration of cefuroxime in the sputum increases with successive doses, reaching mean values of about 2 pg/g which is 4-times above the MIC of cefuroxime for 80% of H . influenzae strains, and these levels are maintained during therapy. Since the concentrations achieved at the end of treatment are high, the degree of sputum purulence does not seem to determine the concentration of cefuroxime achieved. These values are more than 3-times higher than those reported by May and Ingold for ampicillin after 4 g/day and amoxycillin after 2 g / d a ~Bergogne-Berezin .~ and colleagues studied the concentration of cefuroxime achieved in sputum obtained from patients with endotracheal tubes or undergoing fibre-optic bronchoscopy. Concentrations in excess of 2 pg/ml were achieved within 1 hour of a 750 mg intramuscular injection of cefuroxime.2 Cefuroxime sodium was well tolerated both locally and systemically. Rarely did it cause pain which was severe or persistent. Except for one instance of marked diarrhoea and one rash there were no side-effects or toxicity which required interruption of treatment. In conclusion, the results from this large series of patients indicate that cefuroxime is an effective antibiotic in a dose of 750 mg 8-hourly for patients with lower respiratory tract infections requiring parenteral therapy, although a minority of patients may require higher dosage. This new antibiotic is acceptable to patients and is accompanied by only a low risk of side-effects. It would be appropriate now to compare its efficacy, tolerance and safety with established treatments. In the meantime, cefuroxime should be considered as a suitable antibiotic to use alone for treating a wide range of lower respiratory tract infections when parenteral therapy is preferred, and when high concentrations in the serum, tissues and sputum are required without undue risk. Patients with known or suspected H. infuenzae infection, even if the organism produces p-lactamase, and patients who have failed previous oral antibiotic therapy and have been admitted to hospital with a worsening of their lower respiratory tract infection, would seem to be prime candidates. Acknowledgements We are grateful for the co-operation of all the hospital staff who provided the data from their patients to enable us to compile this report.
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Cefuroxime in the treatment of lower respiratory tract infection
Reference 1. Bax, R., (1977). Cefuroxime in the treatment of respiratory tract infections. In: “The Early Evaluation of Cefuroxime”, pp. 11 1-1 16. Eds. : E. S . Snell, C. H. Dash, R. D. Foord and P. W. Muggleton. Glaxo Research Ltd., Greenford. 2. Bergogne-Berezin, E., Even, P., Berthelot, G., and Pierre, J., (1977). Cefuroxime: pharmacokinetic study in bronchial secretions. Proc. R . Soc. Med., 70, Suppl. 9, 34. 3. Laverdiere, M., Wheeler, N., and Sabath, L. D., (1977). Cefuroximeresistance to staphylococcal p-lactamases. Proc. R. Soc. Med., 70, Suppl., 9, 72. 4. May, J. R., and Ingold, A., (1974). Use of amoxycillin in various respiratory infections: lower respiratory tract infections. J. Infect. Dis., 129, Suppl., S189. 5. May, J. R., Hurford, J. V., Little, G. M., and Delves, D. M., (1964). Chemotherapy of chronic bronchitis with large doses of ampicillin. Lancet, 2,444. 6. Muggleton, P. W., (1978). Clinical aspects of the second generation cephalosporin: panel discussion. Scand. J . Infect. Dis., Suppl. 13, 94. 7. O’Callaghan, C. H., (1977). A laboratory evaluation of cefuroxime - a new cephalosporin with stability to P-lactamases. In: “The Early Evaluation of Cefuroxime”, pp. 1-14. Eds.: E. S . Snell, C. H. Dash, R. D. Foord and P. W. Muggleton. Glaxo Research Ltd., Greenford. 8. O’Callaghan, C. H., Sykes, R. B., Griffiths, A., and Thornton, J. E., (1976). Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antinzicrob. Agents Chemother., 9,511. 9. Paterson, I. C., Petrie, G. R., Crompton, G. K., and Robertson, J. R., (1978). Chronic bronchitis: is bacteriological examination of sputum necessary? Br. Med. J., 2,537. 10. Pettersson, T., (1977). Clinical experience in the treatment of pneumonia with cefuroxime. Proc. R. Soc. Med., 70, Suppl. 9, 90. 11. Pines, A., Raafat, H., Taylor-Pearce, M., Nandi, A. R., Hamad, F. A., Kennedy, Margaret R. K., and Mullinger, Brenda M., (1977). Cefuroxime in lower respiratory tract infections. In: “The Early Evaluation of Cefuroxime”, pp. 95-101, Eds.: E. S. Snell, C. H. Dash, R. D. Foord and P. W. Muggleton. Glaxo Research Ltd., Greenford. 12. Richmond, M. H., (1978). p-lactamase insensitive or inhibitory p-lactams: two approaches to the challenge of ampicillin-resistant E. coli. Scand. J . Infect. Di.s., Suppl. 13, 11. 13. Samanta, T., Bax, R., Havard, W., Pearson, R., Brumfitt, W., and Hamilton-Miller, J . , (1978). Cefuroxime in respiratory tract infections, a clinical and pharmacokinetics study. Paper presented at 18th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, U.S.A., 1-4 October. Abstract 316.
718
Vol. 5, No. 10, 1979
-
Cefuroxime in the treatment of lower respiratory tract infection
R. P. Bax,* M.B., B.S., M.R.C.S.,L.R.C.P.,
A. F. Dawson, M.B., Ch.B., Brenda M. Mullinger, B.Sc., and
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C. H. Dash, M.B., Ch.B.,Dip. Pharm.Med., D.Obst.R.C.0.G. Glaxo-Allenbarys Research (Greenford) Ltd., Glaxo Holdings Ltd., London, and Medical Dept., Glaxo Laboratories Ltd., Greenfbrd, England
Curr. Med. Res. Opin., (1979), 5,772.
Received: 20th November 1978
Summary Cefuroxime is ci new parenteral antibiotic with a wider spectrum of activity than earlier cephulosporins arid is particulurly active against Haemophilus influenme, including strains resistant to ampicillin due to j3-lactamuse production. From 18 centres, 274 patients suflering with 275 ir$ections were treated with cefuroxime sodium using the standard regimen of 750 rng 8-hourly by intramuscular injection. The clinical results showed a 90% success rate in the putients with bronchopneumonia (105), 91 % in patients with post-operative pneumonia (74), and 89% in the patients with acute exacerbations of chronic bronchitis (96). Renal function was closely monitored during therupy, and no adverse changes attributable to cefuroxime therapy were seen in any patient, including those M-ho also received frusemide. Two patients (0.7 %) developed a rash, although 8 penicillin-allergic patients were treated without incident, From these studies, it can be concluded that 750 mng refuroxirne 8-hourly is effective in the treatment of lotver respiratory tract infections. It is suggested that the attributes of this antibiotic may offer several advantages over existing therapies. Key Mgords: Cefuroxime - cephalosporins - respiratory tract infections
Introduction Severe lower respiratory tract infection is one of the commonest reasons for hospital admission in the United Kingdom. Bacteriology of sputum is not a reliable method of identifying the pathogen for many reasons ;9 for example, the infection occurs deep in the respiratory tract, and expectorated sputum is often contaminated by commensal organisms. In addition, many patients admitted to hospital with such infections will have already been treated unsuccessfully with a course of oral antibiotics which causes difficulty in interpreting sputum bacteriology. Invasive diagnostic techniques are not justified for the majority of patients but the organisms commonly responsible for lower respiratory tract infections are well known. An ideal antibiotic would be highly active against all these pathogens, particularly those ~~
*Present address: Roussel Laboratories Ltd., Wembley Park, Middlesex, England 172
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R. P. Bax, A, F. Dawson, Brenda M. Mullinger and C . H. Dash
which have become resistant to the commonly prescribed oral antibiotics such as ampicillin and tetracyclines. Such an antibiotic should reliably produce high serum and sputum levels, should be well tolerated by the patient, and be safe to usein everyday clinical practice. Cefuroxime sodium, a new semi-synthetic parenteral cephalosporin antibiotic, appears to have such properties,’ . 1 o,l and encouraging clinical results have been reported from initial clinical studies, although a variety of dosage regimens were used in the early dose-ranging investigations.A comparison of 1 g and 750 mg given 8-hourly showed that the clinical results achieved were similar.’ ~1 Subsequently, emphasis was given to treating lower respiratory tract infections with 750 mg 8-hourly by intramuscular injection and this report summarizes the results.
Patients and methods Two hundred and seventy-four patients (183 male, 91 female) suffering from lower respiratory tract infections have been studied, of whom 230 were treated in nine centres in the United Kingdom and 44 were treated in nine centres overseas. The mean age of the patients was 66 years (range 12 to 92 years). The diagnosis was based on the clinical history and generally accepted physiological and radiological signs. There were 105 patients diagnosed as suffering from bronchopneumonia, 74 with post-operative pneumonia proven radiologically, and 95 with acute exacerbations of chronic bronchitis (including 1 patient who was treated on two occasions). Ninety-three patients (34 %) had previously been given antibiotics for their current infection but these had proved unsuccessful. Patients were treated with 750 mg cefuroxine 8-hourly by intramuscular injection. The duration of therapy was determined by the clinician depending on the individual patient’s response to treatment. Details of history, symptoms and signs, previous antibiotic therapy, concomitant drug therapy, response to treatment, side-effects, if any, and the acceptability of cefuroxime injection were recorded on a standard 10-pageclinical trial record form which ensured uniformity of the data collected. Chest X-rays, bacteriology of sputum, urinalysis and haematological and biochemical tests were performed before and after cefuroxime and, if possible, during treatment. The clinical response to treatment was assessed by the clinician as ‘excellent’ when there was complete remission of symptoms and signs; ‘improved’, a good, adequate clinical response but short of complete remission within the treatment period; and ‘failed’when there was no improvement or worsening. The tolerance of the intramuscular injections was assessed by means of a scoring system for intensity, duration and frequency of pain.
Results Duration of treatment The duration of the treatment was 5 to 8 days for 190 patients, and 9 to 11 days for a further 78. Thus, most of the patients required treatment for 8 days or less. Bacteriological findings Specimens for bacteriological examination were not always obtained from patients 773
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Cefuroximein the treatment of lower respiratory tract infection
before and after treatment, because many patients who had an excellent response to cefuroxime did not produce sputum at the end of therapy and, therefore, were unassessable bacteriologically. However, sputum bacteriology was performed before and after treatment in 128 patients, but in 36 no pathogens were isolated on either occasion. Of the remaining 92 patients (Table I), 72 had their initial organisms eradicated, but in 10 of these Candida albicans was isolated from their post-treatment specimen. Fourteen patients were classified as bacteriological failures because the pathogens present in the pre-treatment samples persisted throughout treatment. Patients classified bacteriologically as ‘partial success’ included those whose initial sputum contained a variety of organisms, some of which persisted at the end of treatment. In only 3 cases were organisms resistant to cefuroxime; Pseudomonas aeruginosa was cultured from the sputum of 2 patients and Serratia marcescens from the third. One of the Ps. aeruginosa and the S. marcescens disappeared from the sputum during the treatment period. Table I. Bacteriological response in 92 patients Diagnosis
Eradicated
Partial success
Bronchopneumonia Post-operative pneumonia Acute exacerbation of bronchitis
35 19 18
2 3 1
5
Total
72
6
14
Persisted
2 7
Ten patients classified as bacteriological failures were judged to have been clinical successes, whereas 6 patients who failed clinically were bacteriological successes (Table 11).Although there seems to be a positive relationship between clinical success and eradication of bacteria, the differences did not reach statistical significance at the 5 % level. Table II. Clinical and bacteriologicalresponse: the percentages are related to the totals shown Clinical results
Bacteriological response Eradicated
Partial success
Persisted
Success Failure
66 (92%) 6 (8%)
5 (83%)
10(71%) 4 (29%)
Total
72
6
1(17%)
Clinicalfindings Amongst the 214 patients there were only 23 patients who were categorized as ‘failed’ at the end of treatment, but an additional 5 relapsed within 7 days of stopping treatment and these have been classified similarly. These 28 patients occurred proportionately in the three diagnostic groups (Table 111). Three patients died during the cefuroximetherapy: 1 of a post-operative aspiration pneumonia and 2 of cerebrovascular accidents. In none of these 3 patients had 774
R. P. Bax, A. F. Dawson, Brenda M. Mullinger and C. H. Dash
Table 111. Clinical response in 275 infections in 274 patients
Diagnosis
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Improved
Failed
Bronchopneumonia Post-operative pneumonia Acute exacerbation of bronchitis
Excellent 65
30
10
45 55
22 30
7 11
Total
165
82
28
there been any improvement of their presenting infection. Over 90 % of those with bronchopneumonia OT post-operative pneumonia responded satisfactorily, as did almost 90% of those with acute exacerbations of chronic bronchitis. Fourteen of the 28 failures had pre-existing diseases, such as severe cardiovascular disease or chronic obstructive airways disease. Clinicians were asked to record the day of relief of symptoms. The majority of patients (84 %) experienced relief of all symptoms by the end of the fourth day of treatment (Figure 1). Figure 1. Day of relief of presenting symptoms
60
20
k
1 2 3
L
Side-e__flects Data on the local discomfort from the injections of cefuroxime sodium were available from 245 patients. Amongst these, 130 (53.1 %) stated that the injections were not painful, 83 (33.9 %) experienced mild pain, 28 (I 1.4%) experienced moderate pain, and only 4 (1.6 %) of the patients experienced severe pain. Thus, 115 patients (47 %) found the injections produced discomfort but only 29 (12 %) found the pain lasted for more than 3 minutes and 4 (1.6 %) for more than 10 minutes. Other side-effects were rare and only occurred in 6 patients. There were two incidents of diarrhoea, both in the patient who had received cefuroxime on two occasions. The second treatment was stopped because of the severityof the diarrhoea. In 2 other patients there were reports of faintness and sweating, but these were probably not related to cefuroxime therapy. Two (0.7 %) further patients developed a rash during cefuroxime therapy and the antibiotic was stopped in one of them. Neither was allergic to penicillin. Eight patients with a history of penicillin-allergy were treated without incident. 775
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Cefuroxirne in the treatment of lower respiratory tract infection
Laboratory Jindings There was no patient who had a clinical episode of acute oliguria or of renal failure due to cefuroxime therapy. Serial estimations of plasma urea and creatinine were carried out in 166 patients before and after treatment. Seventeen patients had received frusemide concurrently. Not uncommonly, the levels of urea and creatinine before and after treatment were different and it is highly likely that these fluctuations represent common random biochemical changes of a minor degree. In order to monitor closely renal tolerance of cefuroxime, the clinical records were carefully scrutinized for all patients whose plasma urea or creatinine concentrations either became abnormal after initially being normal or, if already abnormal, increased further. There were 41 patients in these categories, but in 27 the changes were ascribed to underlying disease by the attendant clinician. Of the remaining 14 patients, 3 patients had an increase in urea of about 1.5mmol/l, 4 of about 2.5 mmol/l, and 1 of 7 mmol/l. Plasma creatinine increased by 20 ymol/l in 3 patients, by 40 :Amol/l in 2, and by 55 pmol/l in another. Significantly, in no patient was there an increase in both urea and creatinine and it is not likely that these changes signify impairment of renal function. Moreover, there was a number of patients with abnormally high levels of plasma creatinine or urea before treatment and in many of these the values were normal at the end. For plasma urea this occurred in 12 of 29 patients, and for creatinine in 3 of 6. Hence, it is concluded that there were no adverse changes in renal function due to treatment with cefuroxime.
Discussion and Conclusions The patients were selected by the clinicians as those whose condition merited intramuscular antibiotics. The overall results are very encouraging. Only about 10 % of the patients did not respond satisfactorily and there are several possible reasons. A large proportion of these had complicating chronic cardiopulmonary disease which may have been a factor in the lack of response. However, other patients with apparently similar complications responded satisfactorily. It is possible that the infections which did not respond were more severe and should have been treated with a larger dose of cefuroxime, e.g. 1.5 g intravenouslyevery 8 hours. The causative bacteria may have been resistant to cefuroxime but, of the bacteria isolated in this study, only 3 were found to be resistant, and 2 ofthese disappeared during cefuroxime treatment. In previous in vitro studies, very few bacteria liable to infect the lower respiratory tract have been resistant.’ Cefuroxime is consistently and highly active against Haemophilus injuenzae, even those strains resistant to ampicillin through production of P-lactamase. This enzyme hydrolyses the P-lactam bond of ampicillin destroying its antibacterial activity. Although some other cephalosporins have a degree of resistance to this enzyme, they are less resistant than cefuroxime, cannot penetrate the bacterial cell wall so rapidly and, consequently, are not effective. A range of similar enzymes are produced by other Gram-negativebacteria which can infect the lower respiratory tract, such as Klebsiella pneumoniae and Escherichia coli. Cefuroxime is active against these bacteria, largely because of marked stability to 776
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R . P. Bax, A. F. Dawson, Brenda M. Mullinger and C. H . Dash
their p-lactamases,7.8 easy penetrability of the outer cell wall, and specificity for the transpeptidases crucial for cell viability.6 Similarly, cefuroxime is stable to the :J-lactamase (penicillinase) produced by staphylococci.3 Bacteria such as Streptococcus pneumoniue and Streptococcus pyogenes, which are sensitive to a wide range of antibiotics, are sensitive to cefuroxime. A small number of patients in this study, although improved at the end of treatment, relapsed with a few days. These patients were included in the clinical failures. The relapses in chronic bronchitics have been associated with the concentration of antibiotics in the sputum, particularly with ampicillin and amo~ycillin.~.5 It has been shown that within 1 hour of the first intramuscular dose of cefuroxime, a mean concentration of 0.8 pg/g of expectorated sputum can be expected13 which is above the minimum inhibitory concentration (MIC) for 80% of strains of H . infuenzue, and above the MIC for all Str. pneumoniue and Str. pyogenes. The concentration of cefuroxime in the sputum increases with successive doses, reaching mean values of about 2 pg/g which is 4-times above the MIC of cefuroxime for 80% of H . influenzae strains, and these levels are maintained during therapy. Since the concentrations achieved at the end of treatment are high, the degree of sputum purulence does not seem to determine the concentration of cefuroxime achieved. These values are more than 3-times higher than those reported by May and Ingold for ampicillin after 4 g/day and amoxycillin after 2 g / d a ~Bergogne-Berezin .~ and colleagues studied the concentration of cefuroxime achieved in sputum obtained from patients with endotracheal tubes or undergoing fibre-optic bronchoscopy. Concentrations in excess of 2 pg/ml were achieved within 1 hour of a 750 mg intramuscular injection of cefuroxime.2 Cefuroxime sodium was well tolerated both locally and systemically. Rarely did it cause pain which was severe or persistent. Except for one instance of marked diarrhoea and one rash there were no side-effects or toxicity which required interruption of treatment. In conclusion, the results from this large series of patients indicate that cefuroxime is an effective antibiotic in a dose of 750 mg 8-hourly for patients with lower respiratory tract infections requiring parenteral therapy, although a minority of patients may require higher dosage. This new antibiotic is acceptable to patients and is accompanied by only a low risk of side-effects. It would be appropriate now to compare its efficacy, tolerance and safety with established treatments. In the meantime, cefuroxime should be considered as a suitable antibiotic to use alone for treating a wide range of lower respiratory tract infections when parenteral therapy is preferred, and when high concentrations in the serum, tissues and sputum are required without undue risk. Patients with known or suspected H. infuenzae infection, even if the organism produces p-lactamase, and patients who have failed previous oral antibiotic therapy and have been admitted to hospital with a worsening of their lower respiratory tract infection, would seem to be prime candidates. Acknowledgements We are grateful for the co-operation of all the hospital staff who provided the data from their patients to enable us to compile this report.
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Cefuroxime in the treatment of lower respiratory tract infection
Reference 1. Bax, R., (1977). Cefuroxime in the treatment of respiratory tract infections. In: “The Early Evaluation of Cefuroxime”, pp. 11 1-1 16. Eds. : E. S . Snell, C. H. Dash, R. D. Foord and P. W. Muggleton. Glaxo Research Ltd., Greenford. 2. Bergogne-Berezin, E., Even, P., Berthelot, G., and Pierre, J., (1977). Cefuroxime: pharmacokinetic study in bronchial secretions. Proc. R . Soc. Med., 70, Suppl. 9, 34. 3. Laverdiere, M., Wheeler, N., and Sabath, L. D., (1977). Cefuroximeresistance to staphylococcal p-lactamases. Proc. R. Soc. Med., 70, Suppl., 9, 72. 4. May, J. R., and Ingold, A., (1974). Use of amoxycillin in various respiratory infections: lower respiratory tract infections. J. Infect. Dis., 129, Suppl., S189. 5. May, J. R., Hurford, J. V., Little, G. M., and Delves, D. M., (1964). Chemotherapy of chronic bronchitis with large doses of ampicillin. Lancet, 2,444. 6. Muggleton, P. W., (1978). Clinical aspects of the second generation cephalosporin: panel discussion. Scand. J . Infect. Dis., Suppl. 13, 94. 7. O’Callaghan, C. H., (1977). A laboratory evaluation of cefuroxime - a new cephalosporin with stability to P-lactamases. In: “The Early Evaluation of Cefuroxime”, pp. 1-14. Eds.: E. S . Snell, C. H. Dash, R. D. Foord and P. W. Muggleton. Glaxo Research Ltd., Greenford. 8. O’Callaghan, C. H., Sykes, R. B., Griffiths, A., and Thornton, J. E., (1976). Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antinzicrob. Agents Chemother., 9,511. 9. Paterson, I. C., Petrie, G. R., Crompton, G. K., and Robertson, J. R., (1978). Chronic bronchitis: is bacteriological examination of sputum necessary? Br. Med. J., 2,537. 10. Pettersson, T., (1977). Clinical experience in the treatment of pneumonia with cefuroxime. Proc. R. Soc. Med., 70, Suppl. 9, 90. 11. Pines, A., Raafat, H., Taylor-Pearce, M., Nandi, A. R., Hamad, F. A., Kennedy, Margaret R. K., and Mullinger, Brenda M., (1977). Cefuroxime in lower respiratory tract infections. In: “The Early Evaluation of Cefuroxime”, pp. 95-101, Eds.: E. S. Snell, C. H. Dash, R. D. Foord and P. W. Muggleton. Glaxo Research Ltd., Greenford. 12. Richmond, M. H., (1978). p-lactamase insensitive or inhibitory p-lactams: two approaches to the challenge of ampicillin-resistant E. coli. Scand. J . Infect. Di.s., Suppl. 13, 11. 13. Samanta, T., Bax, R., Havard, W., Pearson, R., Brumfitt, W., and Hamilton-Miller, J . , (1978). Cefuroxime in respiratory tract infections, a clinical and pharmacokinetics study. Paper presented at 18th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, U.S.A., 1-4 October. Abstract 316.
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