Drugs 42 (Suppl. 3): 34-40. 1991 0012-6667/91/0300-0034/$3.50/0 © Adis International Limited. All rights reserved. DRSUP3237
Cefpodoxime Proxetil in the Treatment of Lower Respiratory Tract Infections A.M. Geddes Department of Communicable and Tropical Diseases, East Birmingham Hospital, Birmingham, England
Cefpodoxime proxetil is the orally absorbed ester of cefpodoxime, a new third generation cephalosporin. In the gastrointestinal tract, cefpodoxime proxetil is hydrolysed to cefpodoxime, which has potent antibacterial activity against the major bacterial pathogens involved in lower respiratory tract infections: Haemophilus influenzae. Moraxella (Branhamella) catarrhalis (including /3-lactamase-producing strains), and Streptococcus pneumoniae (including amoxicillinresistant strains). Six randomised comparative studies in patients with lower respiratory tract infections,S of which were large (enrolment of more than 200 patients) and double-blind, examined the efficacy and safety of cefpodoxime proxetil. Cefpodoxime proxetil (at a dosage equivalent to 200mg of cefpodoxime) administered twice daily for 5 to 10 days was similar in clinical and bacteriological efficacy to the following: amoxicillin 500mg 3 times daily in the treatment of community-acquired pneumonia; intramuscular ceftriaxone Ig once daily in the treatment of pulmonary infections in hospitalised patients; and to amoxicillin/clavulanic acid 500/125mg 3 times daily in the treatment of acute exacerbations of chronic bronchitis (AECB). Additionally, a dosage equivalent to 100mg or 200mg of cefpodoxime twice daily was similar in clinical and bacteriological efficacy to amoxicillin 250mg 3 times daily in the treatment of bronchitis (acute or AECB). The adverse events noted with cefpodoxime proxetil administration were similar to those associated with other /3-lactam antibacterials and most commonly involved the gastrointestinal tract and skin or mucous membranes. Thus, cefpodoxime proxetil is a useful addition to the antibacterials available for the treatment of infections of the lower respiratory tract.
Infections of the lower respiratory tract are possibly the commonest cause of illness in the world. They involve patients of all ages but are particularly severe in the debilitated, smokers, the elderly, and those with chronic lung disorders. Failure to cure an acute infection can lead to chronic lung disease. Community-acquired pneumonia can usually be treated at home, but patients, especially the elderly, may require hospitalisation if the initial therapy is inappropriate or inadequate. In the United Kingdom, Streptococcus pneumoniae is the most frequently encountered bacterial pathogen associated
with community-acquired pneumonia (Venkatesan & Macfarlane 1991). Other respiratory pathogens include Haemophilus injluenzae (especially in the elderly), Staphylococcus aureus (after viral infections such as influenza or measles), Mycoplasma pneumoniae and, less commonly, Legionella pneumophila and Chlamydia spp. (Macfarlane 1987; Venkatesan & Macfarlane 1991). In the immunocompromised and those with chronic lung disease, Gram-negative bacilli such as Escherichia coli and Klebsiella spp. may be responsible (Macfarlane 1987; Venkatesan & Macfarlane 1991). Chronic bronchitis is very common, particu-
Cefpodoxime Proxetil in LRTI
larly in the United Kingdom, accounting for much morbidity and frequently requiring hospitalisation. Acute infective exacerbations of chronic bronchitis (AECB) are usually caused by H. injluenzae or S. pneumoniae, alone or in combination; Moraxella (Branhamella) catarrhalis is being encountered with increasing frequency (Davies & Maesen 1990). Acute bronchitis is usually of viral aetiology, but can be complicated by superinfection with S. pneumoniae or H. injluenzae. The pathogens causing respiratory tract infections are usually susceptible to ~-lactam antibacterials, penicillins and cephalosporins. However, the increasing prevalence of bacteria that produce ~-lactamase enzymes is resulting in a growing incidence of resistance to ampicillin, related penicillins and the earlier cephalosporins, particularly among H. injluenzae and M. catarrhalis. Additionally, the presence of bacteria-producing ~-lacta mases, even if not the primary pathogens, may interfere with the action of ~-lactam antibacterials against the specific pathogenic bacteria. Microbiological confirmation is seldom available at the time of diagnosis, particularly in lower respiratory tract infections, for which sputum culture may be insufficient. Thus, the clinician often has to select an antibacterial on a 'best guess' basis, which requires the prescription of a broad spectrum antibacterial, particularly in patients who are moderately or seriously ill. The cephalosporins, which were first introduced in the mid-1960s, were the first ~-lactam antibacterials to have a broad antibacterial spectrum. Since then, research has produced more microbiologically active cephalosporins, especially against Gram-negative organisms, and also some that are particularly stable in the presence of ~-lactamases. Unfortunately, until recently, most of these potent cephalosporins, such as cefotaxime and ceftazidime, could only be administered by intravenous or intramuscular injection, thus necessitating hospitalisation. However, third generation oral cephalosporins have recently been developed. Because of their broad antibacterial spectrum, the cephalosporins have proved valuable for the treatment of respiratory tract infections, particularly acute ex-
acerbations of chronic bronchitis (AECB) and bronchopneumonia, which are frequently caused by more than one organism. The newer ~-lacta rnase-stable oral cephalosporins, such as cefpodoxime proxetil, are of potential value for these indications. The purpose of this review is to report the microbiological and pharmacological bases for the use of cefpodoxime proxetil in lower respiratory tract infections, and the clinical studies assessing safety and efficacy in these indications.
1. In Vitro Activity Cefpodoxime has exceptionally good actIvIty against S. pneumoniae, its bactericidal action being similar to that of benzylpenicillin and amoxicillin against penicillin-susceptible strains, with activity maintained against strains with reduced susceptibility to penicillin and amoxicillin (Dabernat et al. 1990). Cefpodoxime is also very active against H. injluenzae. including ~-lactamase-producing strains (Dabernat et al. 1990). Compared with currently available oral cephalosporins, such as cefaclor and cefixime, cefpodoxime is comparatively active against pneumococci with reduced susceptibility to penicillin (Dabernat et al. 1990). It is also significantly more active than cefaclor, cefalexin and cefuroxime against H. injluenzae (Dabernat et al. 1990; Holt et al. 1990). Against ~-lactamase-producing strains of M. catarrhalis, the activity of cefpodoxime is greater than that of amoxicillin and cefaclor, but equivalent to that of amoxicillin/clavulanic acid (Dabernat et al. 1990; Holt et al. 1990). Against S. pyogenes. cefpodoxime is 8 to 16 times more active than cefaclor and cefalexin, although this pathogen is highly susceptible to all of these cephalosporins (Dabernat et al. 1990; Holt et al. 1990).
2. Pharmacokinetics ~-Lactam antibacterials have traditionally been prescribed in 500mg doses administered every 6 or 8 hours. The high in vitro activity of cefpodoxime against most bacterial respiratory pathogens led the manufacturers to explore the possibility of a lower
Drugs 42 (Suppl. 3) 1991
unit dose. Figure I shows the plasma concentrations of cefpodoxime after administration of cefpodoxime proxetil (200mg cefpodoxime equivalent) to young and elderly patients with respiratory tract infections. Table I summarises the concentrations of cefpodoxime achieved in the lower respiratory tract from 3 to 12 hours after administration of single oral doses of cefpodoxime proxetil (200mg cefpodoxime equivalent) to patients undergoing thoracotomy for suspected pulmonary neoplasm (lung tissue) or with pleural effusions (pleural fluid). Clearly, serum and respiratory tissue and fluid concentrations of cefpodoxime are adequate for the inhibition of important respiratory pathogens such as M. catarrhalis. H. influenzae. S. pyogenes. and S. pneumoniae. The long half-life (2-3h) [Wise 1990] suggests that cefpodoxime proxetil could be administered every 12 hours instead of 8-hourly or 6-hourly.
3. Clinical Efficacy in Lower Respiratory Tract Infections In the following discussion, doses of cefpodoxime proxetil will be reported as the cefpodoxime equivalent. Preliminary clinical trials in South Africa and Japan confirmed that cefpodoxime proxetil 100 and 200mg twice daily were effective in the treatment of respiratory tract infections which included pneumonia (Safran 1990). As a result, these doses were retained for the subsequent clinical trial programme. As summarised in table II, the efficacy of cefpodoxime proxetil has been evaluated in 6 randomised comparative studies, 5 of them double-blind, involving 1582 adult patients (1033 cefpodoxime proxetil; 549 comparator). Infections treated in-
4 M. catarrhalis (MICgO 0.5 mg/L)
:::J 0; 3 .§.
H. influenzae (MICgO 0.05 mg/L)
E Ql (J
S. pneumoniae (MICgO 0.06 mg/L)
(MICgo 0.015 mg/L)
Time (hours) Fig. 1. Plasma concentration-time curves (mean ± SO) for cefpodoxime in 15 young (_) and 9 elderly (0) patients with respiratory tract infections. after the last morning dose of a 6- to lO-day regimen of cefpodoxime proxetil (200mg cefpodoxime equivalent) twice daily (after Backhouse et al. 1990; M1C90 data after Holt et al. 1990). M1C90 = minimum concentrations required to inhibit 90% of pathogens.
Cefpodoxime Proxetil in LRTI
Table I. Fluid and tissue concentrations of cefpodoxime (values are ± SEM) after a single oral dose of cefpodoxime proxetil (200mg cefpodoxime equivalent) [after Couraud et al. 1990; Dumont et al. 1990; and Wise & Andrews, personal communication] Time (hours)
Pleural fluid (mg/L) [n = 6]
Lung (mg/kg) [n
0.62 ± 0.19 1.84 ± 0.33 0.78 ± 0.10
0.63 ± 0.16 0.52 ± 0.09 0.19 ± 0.02
Bronchial mucosa (mg/kg) [n = 3] 1.08 ± 0.14 ND ND
Abbreviation: ND = not determined.
eluded acute bronchitis, AECB, community-acquired pneumonia, and pneumonia in hospitalised patients with at least one of the following risk factors: age ~ 65 years, chronic alcoholism, smoking, diabetes, drug addiction, malnutrition, or other significant diseases.
3.1 Pneumonia The efficacy of cefpodoxime proxetil in the treatment of community-acquired pneumonia has been shown in 2 large double-blind comparative studies (table II).
Table II. Randomised controlled comparisons of the efficacy of oral cefpodoxime proxetil (CPD) in adults with lower respiratory tract infections Reference
Study design (no. of patients)
Community-acquired pneumonia Sieling et al. (1989) Double-blind (200) Leophonte et al. (1989)
Pulmonary infections in at-risk inpatients b Zuck et al. (1990) Open (96) BronchitisC Data on file, Roussel Uclaf Data on file, Roussel Uclaf
Double-blind (426) Double-blind (402)
Infectious exacerbation of chronic bronchitis Periti et al. (1990) Double-blind (251)
Evaluable patients showing a satisfactory response at end of treatment (%) clinical
CPD 100mg bid CPD 200mg bid CPD 200mg bid Amoxicillin 500mg tid
93/95 93/93 75/83 77/83
58/61 51/56 42/42 44/47
CPD 200mg bid Ceftriaxone 19 1M qd
43/44 (97.7) 39/41 (95.1)
33/35 (94.3) 37/38 (97.4)
CPD 100mg bid Amoxicillin 250mg tid CPD 200mg bid Amoxicillin 250mg tid
208/243 (85.6) 107/121 (88.4) 189/219 (86.3) 100/116 (86.2)
101/108 (93.5) 46/54 (85.2) 97/103 (94.2) 47/53 (88.7)
(97.9) (100) (90.4) (92.8)
CPD 200mg bid 103/106 (97.2) Amoxicillin/clavulanic acid 108/114 (94.7) 500/125mg tid
(95.1) (91.1) (100) (93.6)
12/15 (80.0) 16/22 (72.7)
Dosage of cefpodoxime proxetil expressed as cefpodoxime equivalents. Risk factors included age ~ 65 years, chronic alcoholism, smoking, diabetes, drug addiction, malnutrition, or other significant diseases. c Acute bronchitis or infectious exacerbation of chronic bronchitis. Abbreviations: bid = twice daily; qd = once daily; 1M = intramuscularly.
The first, a dose-response study conducted in South Africa, established the equivalent bacteriological and clinical efficacy of 100 and 200mg doses of cefpodoxime proxetil administered twice daily for 5 to 10 days (Sieling et al. 1989). In this study, S. pneumoniae was the most frequently isolated pathogen, accounting for 68% of the isolates; 18% of the isolates were Haemophilus spp. and 8% were Klebsiella spp. The mean duration of therapy was 7 days in each group. Clinical cure was established in 93 of95 (97.9%) evaluable patients in the 100mg group and in all 93 patients in the 200mg group, while bacteriological efficacy was obtained in 58 of 61 (95.1%) and 51 of 56 (91.1%) bacteriologically evaluable patients, respectively. A further study, conducted in Europe and Argentina, compared cefpodoxime proxetil 200mg twice daily with amoxicillin 500mg 3 times daily (Leophonte et al. 1989). The duration of therapy varied from 5 to 10 days. Microbiological confirmation of the diagnosis of pneumonia was obtained in 112 (60.7%) patients. As in the previous study, the commonest infecting organism was S. pneumoniae, followed by H. injluenzae. The overall clinical and bacteriological response was similar in both treatment groups, with a satisfactory clinical response in 75 of 83 (90.4%) and 77 of 83 (92.8%) evaluable patients in the cefpodoxime proxetil and amoxicillin groups, respectively, and a satisfactory bacteriological response in all 42 (100%) and in 42 of 47 (93 .6%) patients, respectively. Hospitalised patients with pneumonia and one or more additional risk factors (e.g. age;;?; 65 years, chronic alcoholism, smoking, diabetes, drug addiction, malnutrition, or other significant diseases) were assessed by Zuck et al. (1990) in a randomised open label study. Cefpodoxime proxetil was administered at a dosage of 200mg twice daily, and compared with ceftriaxone (an injectable long-acting cephalosporin) administered intramuscularly at a dosage of Ig once daily. Both groups of patients were treated for 10 days. Bacteriological confirmation of pneumonia was obtained in most patients, and the infecting organisms included pneumococci (46% of cases), H. injluenzae (38%), Klebsiella spp. (6%) and other Gram-negative ba-
Drugs 42 (Suppl. 3) 1991
cilli. At the end of treatment, overall clinical efficacy, defined as cure or improvement, was similar in the treatment groups (cefpodoxime proxetil 97.7%; ceftriaxone 95.1%); there was also similarity between the groups in bacteriological response, with bacterial eradication (or clinical cure preventing further sputum production) of 94.3% and 97.4% of pretreatment isolates, respectively. At day 30, the bacteriological response was satisfactory in all patients available for evaluation (62 pathogens, 55 patients). Similarly, at follow-up, 68 of 69 evaluable patients had a satisfactory clinical response, the sole unsatisfactory response being in a patient treated with ceftriaxone. 3.2 Bronchitis Two comparative randomised double-blind trials were conducted in the UK in patients suffering from acute bronchitis or AECB. In both studies, cefpodoxime proxetil was compared with amoxicillin at a dosage of 250mg 3 times daily, and the duration of therapy was 7 days. Causative pathogens were isolated from 40% of the patients recruited. Pathogens isolated were Haemophilus (48%), B. catarrhalis (10%), S. pneumoniae (10%), S. aureus (6%), or a mixed growth of these pathogens (25%). Cefpodoxime proxetil, whether at a dosage of 100mg twice daily or 200mg twice daily, was similar in clinical efficacy to amoxicillin but eradicated a greater percentage of pathogens (table II). When subgroup analysis was conducted, the tendency towards greater bacteriological efficacy with cefpodoxime proxetil was more pronounced in the subgroup of patients with AECB (table III), a condition which is more difficult to treat. An additional comparative double-blind randomised trial examined the efficacy of cefpodoxime proxetil 200mg twice daily in a population consisting solely of patients with AECB (Periti et al. 1990). Amoxicillin/c1avulanic acid 500/1 25mg 3 times daily was used as the comparative agent, and both treatments were continued for a duration of 10 days. Causative organisms were cultured from only 57 of the 251 patients enrolled; in the 37 bacteriologically evaluable patients, H. injluenzae was
Cefpodoxime Proxetil in LRTI
Table III. Subgroup analysis of two UK randomised double-blind comparisons of oral cefpodoxime proxetil (CPO) and amoxicillin (AMX) in adults with bronchitis Reference
Data on file , Roussel Uclaf Data on file, Roussel Uclaf
Dosage a (no. of patients)
CPO 100mg bid AMX 250mg tid (426) CPO 200mg bid AMX 250mg tid (402)
Evaluable patients showing a satisfactory response at end of treatment (%) bacteriological
clinical acute bronchitis
132/148 (89.2) 65/68 (95.6)
76/95 (80.0) 42/53 (79 .2)
67/68 (98.5) 26/27 (96.3)
34/40 (85 .0) 20/27 (74 .1)
125/145 (86.2) 73/83 (88.0)
64/74 (86.5) 27/33 (81.8)
67/71 (94 .4) 38/41 (92 .7)
30/32 (93.8) 9/12 (75.0)
a Dosage of cefpodoxime proxetil expressed as cefpodoxime equivalents. Abbreviations: AECB = acute exacerbations of chronic bronchitis; bid = twice daily; tid
the most frequentl y isolated pathogen (25%), followed by S. aureus (18%), M. catarrhalis (18%) and S. pneumoniae (10%). Clinical efficacy, defined as cure or improvement, was obtained in 103 of 106 (97.2%) evaluable patients treated with cefpodoxime proxetil, compared with 108 of 114 (94.7%) evaluable patients treated with amoxicillin/cIavulanie acid (table II). Approximately 100 patients from each group were evaluable at the follow-up visit, 6 to 47 days post-treatment; one patient in the cefpodoxime proxetil group and 2 patients in the amoxiciliin/cIavulanic acid group had either a new or persisting infection after a previous clinical improvement.
4. Tolerance Ten phase II and phase III studies of upper and lower respiratory tract infections have been conducted in Europe, South Africa, and South America. In these studies, cefpodoxime proxetil (equivalent to 100mg or 200mg of cefpodoxime) was administered twice daily for 5 to 10 days to 1468 patients (855 men and 613 women) ranging in age from II to 93 years. As reviewed by Safran (1990), adverse events were reported in 144 (9.8%) of the 1468 patients. None were severe and all were reversible. The principal adverse event involved the gastrointestinal tract (table IV). Clostridium difficile was cultured from the stool in 3 patients, only
= 3 times daily.
one of whom had severe diarrhoea. The second most common adverse event involved the skin or mucous membranes.
5. Discussion Cefpodoxime is highly active in vitro against the 3 common causes of respiratory tract infections, S. pneumoniae, H. injluenzae and M. catarrhalis (Holt et al. 1990). It is less active against S. aureus, and is inactive against M . pneumoniae and L. pneumophila, the causes of atypical pneumonia. Table IV. Adverse events reported in at least 1% of patients administered cefpodoxime proxetil (1468 patients) or comparative antibacterials (804 patients) in phase II and phase III doubleblind clinical trials of lower and upper respiratory tract infections (after Safran 1990) Adverse event
Digestive system Diarrhoea Nausea Abdominal pain Skin and mucosa rash a b
No. of patients (%) cefpodoxime proxetil a
67 (4.6%) 18(1 .2%) 18 (1.2%)
28 (3.5%) 8 (1.0%) 10(1 .2%)
9 (1 .1%)
Dosage given as cefpodoxime equivalent. Amoxicillin. amoxicillin/clavulanic acid, ceftriaxone , cefuroxime. phenoxy methyl penicillin, and cefaclor.
Because of the high activity of cefpodoxime and its relatively long serum half-life compared with many other antibacterials, it is possible to administer it in doses of only 100 or 200mg. every 12 hours. The lower dose is indicated for less severe lower respiratory tract infections, such as acute bronchitis, while the 200mg dose is indicated for other infections of the respiratory tract. The present review described 6 randomised comparative studies of cefpodoxime proxetil in patients with lower respiratory tract infections. Five of these studies were large (enrolment of more than 200 patients) and double-blind. Cefpodoxime proxetil (in a dosage equivalent to 100 or 200mg of cefpodoxime) was administered twice daily for 5 to 10 days. The results of these studies show that cefpodoxime proxetil is similar in clinical and bacteriological efficacy to comparative antibacterials commonly used for the treatment of lower respiratory tract infections, such as amoxicillin and amoxicillin/clavulanic acid, and is comparable to intramuscular ceftriaxone Ig once daily in inpatients with pneumonia and at risk because of underlying diseases or malnutrition, advanced age, chronic alcoholism, smoking, diabetes, or drug addiction. Cefpodoxime was well tolerated by human volunteers and also by patients. Among the 1468 patients in phase II and phase III clinical trials in Europe, South Africa and South America, the commonest adverse events involved the gastrointestinal tract and skin. None of the adverse events were serious and all were reversible. In a leading article in the Journal of Antimicrobial Chemotherapy, on the treatment of respiratory tract infections, Davies and Maesen (1990) stated, 'What is clearly needed for therapy is an oral regimen which is highly effective against the "Big Three" respiratory pathogens (s. pneumoniae, H. injluenzae and B. catarrhalis), including the t3-lactamase producing strains.' Cefpodoxime proxetil fulfils these criteria and is a useful addition to the antibacterials available for the treatment of lower respiratory tract infections, and should lead to more effective management of such infections, possibly avoiding hospital admission in some cases.
Drugs 42 (Suppl. 3) 1991
It has the advantage of a good antimicrobial spec-
trum, satisfactory absorption from the intestinal tract, good penetration into the tissues of the respiratory tract, and a low incidence of side effects.
References Backhouse C. Wade A, Williamson P. Tremblay D. Lenfant B. Multiple dose pharmacokinetics of cefpodoxime in young adult and elderly patients. Journal of Antimicrobial Chemotherapy 26 (Suppl. E): 29·34, 1990 Couraud L, Andrews JM. Lecoeur H. Sultan E. Lenfant B. Con· centrations of cefpodoxime in plasma and lung tissue after a single oral dose of cefpodoxime proxetil. Journal of Antimi· crobial Chemotherapy 26 (Suppl. E): 35-40. 1990 Dabernat H, Avril JL. Boussougant Y. In vitro activity of cefpo· doxime against pathogens responsible for community·acquired respiratory tract infections. Journal of Antimicrobial Chemo· therapy 26 (Suppl. E): 1-6. 1990 Davies BI. Maesen FPV. Treatment of Branhamella catarrhalis infections. Journal of Antimicrobial Chemotherapy 25: 1-7. 1990 Dumont R. Guetat F. Andrews JM. Sultan E. Lenfant B. Con· centrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil. Journal of Anti· microbial Chemotherapy 26 (Suppl. E): 41-46. 1990 Holt HA. Bywater MJ. Reeves DS. In·vitro activity of cefpodox· ime against 1834 isolates from domiciliary infections at 20 UK centres. Journal of Antimicrobial Chemotherapy 26 (Suppl. E): 7·23. 1990 Leophonte P. Rouquet RM. Gustin M. et al. Cefpodoxime prox· etil I'S amoxycillin in the treatment of community-acquired pneumonia in adult patients. Abstract 653. International Con· gress for Infectious Diseases. Montreal. Canada, July 15·19. 1990 Macfarlane JT. Treatment of lower respiratory infections. Lancet 2: 1446·1449. 1987 Periti P. Novelli A. Schildwachter G. Schmidt·Gayk H. et al. Ef· ficacy and tolerance of cefpodoxime proxetil compared with co·amoxiclav in the treatment of exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 26 (Suppl. E): 63-70, 1990 Safran C. Cefpodoxime proxetil: dosage, efficacy and tolerance in adults suffering from respiratory tract infections. Journal of Antimicrobial Chemotherapy 26 (Suppl. E): 93·10\, 1990 Sieling W, Calver A, Dansey R, Davies T, et al. Cefpodoxime proxetil (RU 51807) in the treatment of adult community ac· quired pneumonias (a multicenter study). 16th International Congress of Chemotherapy, Jerusalem, June 11·16, 1989 Venkatesan P, Macfarlane JT. Epidemiology, pathogenesis and prevention of pneumonia. Current Opinion in Infectious Dis· eases 4: 145-149, 1991 Wise R. The pharmacokinetics of the oral cephalosporins - are· view. Journal of Antimicrobial Chemotherapy 26 (Suppl. E): 13·20, 1990 Zuck P, Rio Y, Ichou F. Efficacy and tolerance of cefpodoxime proxetil compared with ceftriaxone in vulnerable patients with bronchopneumonia. Journal of Antimicrobial Chemotherapy 26 (Suppl. E): 71-78, 1990
Correspondence and reprints: Prof. A.M. Geddes, Department of Communicable and Tropical Diseases, East Birmingham Hospi· tal, Bordesley Green East, Birmingham B9 5ST, England.