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Saturday 6 February 1982

CEFUROXIME VERSUS AMPICILLIN ANDCHLORAMPHENICOL FOR THE TREATMENT OF

BACTERIAL MENINGITIS

Report from a Swedish Study Group*

Summary In a prospective randomised multicentrestudy cefuroxime was compared with a

combination of ampicillin and chloramphenicol in thetreatment of 50 consecutive patients with acute bacterialmeningitis, in 40 of whom the bacterial aetiology was provenby cerebrospinal-fluid (CSF) cultures. Excellent clinicalresults were obtained in 18 of 21 evaluable patients treatedwith cefuroxime and in 14 of 19 evaluable patients treatedwith ampicillin and chloramphenicol. The meningitis wascaused by Haemophilus influenzae in 20 of the evaluablepatients, by meningococci in 11, by pneumococci in 5, and byother bacterial species in 4. Two of the H. influenzae strainswere &bgr;-lactamase producing, and the 2 patients infected withthese strains, 1 in each treatment group, were cured. 4 of thepatients died from their infections. 3 of these patients, 1 in thecefuroxime group and 2 in the ampicillin pluschloramphenicol group, were children who were admitted inextremely poor condition. The 4th patient had a

staphylococcal abscess in the hip which was not recognisedand drained. He recovered from his meningitis but died frombrain abscesses. In 1 patient in the cefuroxime group and 2patients in the ampicillin plus chloramphenicol group therewas incomplete resolution of symptoms or complications haddeveloped by the end of the treatment period. At follow-up 6weeks after the end of the treatment period 1 patient in the

*The study group included: 0. JOHANSSON, M.D., Department ofPaediatrics, Malmö General Hospital; S. CRONBERG, M D. and B.HOFFSTEDT, M.D., Department of Infectious Diseases, MalmöGeneral Hospital; M. WALDER, M.D., Department of ClinicalBacteriology, Malmö General Hospital; M. ERIKSSON, M.D.,

Department of Paediatrics, St. Goran’s Hospital, Stockholm;B. JOHANSSON, M.D. and M. HAGLUND, M.D., Department ofPaediatrics, Huddinge Hospital; A. S. MALMBORG, M.D.,Department of Clinical Bacteriology, Huddinge Hospital;K. ALESTIG, M.D., Department of Infectious Diseases, University ofGothenburg; J. E. BRORSON, M.D., Department of Clinical

Bacteriology, University of Gothenburg; L. GoTHEFORS, M.D. andS. ENGBERG, M D., Department of Paediatrics, University ofUmeafL. A. BURMAN, M.D, Department of Infectious Diseases, Universityof Umeå; S. HOLM, M.D., Department of Clinical Bacteriology,University of Umea.The scientific coordinator was PROF R. NORRBY, M.D.,

Department of Infectious Diseases, University of Umea, and thechairman of the coordinating group was PROF F. NORDBRING, M.D.,Department of Infectious Diseases, University of Lund.

cefuroxime group showed a hearing defect not noted ondischarge from hospital. No serious adverse reactions werenoted. Determination of CSF and serum concentrations ofcefuroxime 6-12 h after a dose showed a high degree ofpenetration of cefuroxime through the blood-CSF barrier.Cefuroxime is an alternative for treatment of acute bacterial

meningitis in children and adults.

Introduction

MOST cases of bacterial meningitis in children and adultsnot compromised by immune defects are caused byHaemophilus influenzae, Streptococcus pneumoniae, or

Neisseria meningitidis. Since the prognosis for these patientsgreatly depends on the rapid institution of effectiveantibacterial treatment, the initial choice of antibiotics shouldinclude drugs which are active against all three species and areable to penetrate the blood-brain barrier in quantitiessufficient to give therapeutic concentrations in the

cerebrospinal fluid (CSF). Ampicillin, benzylpenicillin,chloramphenicol, or a combination of chloramphenicol andone of the others have been first choices for treatment ofbacterial meningitis. However, these drugs are no longerlikely to be effective against all cases of meningitis caused byH. influenzae or Str. pneumoniae. The frequency of

3-lactamase-producing strains of H. influenzae has greatlyincreased during the past 10 years, and scattered cases ofinfection with chloramphenicol-resistant H. influenzae andpneumococci have been reported.’-4 The reports fromvarious parts of the world on decreased penicillinsusceptibility of some pneumococcal strains suggest thatbenzylpenicillin may be less valuable in treatment of

meningitis caused by these organisms.’-’ There has thereforebeen a search for new antibiotics effective in the treatment of

meningitis. Despite the disappointing results obtained withcephalothin or cephaloridine in acute bacterial meningitis,8the main interest has focused on the new cephalosporins.These agents have greater resistance to hydrolysis by(3-lactamases than the older cephalosporins, and they arehighly active against H. influenzae. Their activity againstpneumococci is similar to that of benzylpenicillin, but onlylimited information is available on their effectiveness againstorganisms less susceptible to penicillin.s Reports9-13 havebeen published on the use of cefuroxime, cefamandole,cefotaxime, moxalactam, or cefoxitin in the treatment ofbacterial meningitis. In all of these studies only selectedpatients were treated, and the cephalosporin was often givenin combination with other antibiotics; the studies were openand uncontrolled. We have undertaken a multicentre opencontrolled study in which the effects of treatment with

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cefuroxime in consecutive patients with bacterial meningitiswere compared with those of treatment with a combination ofchloramphenicol and ampicillin.

Patients and Methods

Study DesignFour paediatric departments and three departments of infectious

diseases in university hospitals in Sweden participated in the study.Under the protocol adults and children with suspected acutebacterial meningitis would be randomly allocated to treatment witheither cefuroxime alone or a combination of ampicillin andchloramphenicol. The protocol excluded patients who had hadserious allergic reactions to penicillins or cephalosporins, infantsunder 3 months of age, patients with known immunosuppression,patients with intraventricular shunts, patients with urinary-tractmalformation, pregnant women, and patients in whom thecausative organism was suspected of being resistant to cefuroximeor to both ampicillin and chloramphenicol. (No patients wereexcluded under the last provision, however.) The treatment alloca-tion was unknown to the attending physician until a decision toinclude the patient had been made. Oral informed consent wasobtained from all patients or, when the patient was under the legalage of consent or for medical reasons unable to give such consent,from a relative. The protocol of the study was approved by theethical committees of the faculties of medicine at the universities ofthe participating departments.

Patients .

During the period between March 31, 1980, and April 30, 1981,67 patients were enrolled in the study. 35 patients were allocated totreatment with ampicillin and chloramphenicol (A+ C group) and32 to treatment with cefuroxime (CXM group). 17 of the patientswere found not to have purulent meningitis and were not includedin the evaluation of efficacy of the test regimens. The remaining 50patients all had clinical symptoms and CSF findings consistent withpurulent meningitis. 10 of these patients had to be excluded fromthe efficacy evaluation because the aetiology could not be verifiedbacteriologically (4 patients) or because the test drugs were notadministered according to the protocol (6 patients). 6 of thesepatients had been allocated to the A+ C group and 4 to the CXMgroup. 8 of them recovered from their infections. 1 patient withH. influenzae meningitis in each group showed signs of braindamage on discharge from hospital. In 40 patients, 21 in the CXMgroup and 19 in the A+ C group, the aetiology was verified andtreatment was given according to the protocol. The demographiccharacteristics of these patients are given in table I.

Antibiotic Treatment

Cefuroxime (’Zinacef, Glaxo, U.K.) was administered every 8 hin doses of 60-75 (mean 68) mg/kg body weight to the children.Adults received 3 g 8-hourly, corresponding to 40-67 (mean 47)mg/kg body weight.- In the A+ C group the mean ampicillin dose to children was 70(range 50-75) mg/kg body weight every 6 h. Adult patients received3 g every 6 h, corresponding to 38-61 (mean 51) mg/kg body weight.Chloramphenicol was given to adults in doses 1/4 of the ampicillindose. The children received 22-25 (mean 24 mg) of

chloramphenicol per kg body weight every 6 h. The protocolrequired patients in the A+ C group to be treated with both drugsfor 5 days before treatment was changed to either ampicillin alone orchloramphenicol alone The minimum treatment time was 5 days.At the end of the treatment period the outcome of the infections

was evaluated in each of these patients. When there was completeresolution of all symptoms and there were no complications duringtreatment, the patients were considered cured. Improvement wasdefined as resolution of most but not all of the symptoms, or

appearance of complications during treatment, or both. In additionto the evaluation after treatment and on discharge from hospital allpatients but 2, who failed to appear, were seen 6 weeks afterdischarge. At that visit all patients were tested for possible hearingdefects subjectively or by audiometry.

TABLE I-DEMOGRAPHIC CHARACTERISTICS OF EVALUABLE PATIENTS

Laboratory TestsOn admission to hospital a lumbar puncture was carried out and

the numbers of cells and concentrations of protein and glucose inthe CSF were measured. Samples of CSF and blood and specimensfrom other appropriate sites were taken for culture. Antibiotic-susceptibility tests were carried out by means of a paper-discdiffusion test with defined cut-off points for sensitivity andresistance.14 In most patients a second CSF sample was takenwithin 48 h of the start of the treatment and examined in the same

way. That specimen was obtained as short as time as possible beforea new dose of the test drug or drugs and, when sufficient volume wasobtained, CSF concentrations of cefuroxime or chloramphenicolwere assayed with an agar-well technique. The test strains used wereBacillus subtilis 1904 E (Glaxo Group Research, U.K.) forcefuroxime assays and Micrococcus luteus ATCC 9341 for

chloramphenicol assays. The medium used was antibiotic mediumno. 2 (Oxoid) supplemented with sodium citrate 3 g/1 for cefuroximeassays and with penicillinase (25 000 units/ml; Leo, Helsingborg,Sweden) for chloramphenicol assays. Chloramphenicol or

cefuroxime concentrations were also determined in serum samplestaken at the same time as the CSF samples by the techniquesdescribed above. Each batch of tests included standards ofcefuroxime or chloramphenicol prepared in CSF or serum. Inaddition an ampicillin control was included in all chloramphenicolassays to confirm that the penicillinase was effective. Allconcentration assays were carried out at the department of clinicalbacteriology, Malmö General Hospital. The samples were stored at- 20°C (by the original investigators) or -70°C (at the assayinglaboratory) until analysed.

Results

Clinical and Bacteriological Results

Excellent clinical results with complete resolution of

symptoms were recorded in 18 of the 21 patients in the CXMgroup and in 14 of the 19 patients in the A+ C group. Thecausative pathogens and the clinical outcome of the treatment for the evaluable patients are given in table 11. In bothgroups the most commonly isolated bacterial species wasH. influenzae. Two of the strains isolated, one in each treat-ment group, produced &bgr;-lactamase. Importantly, the twopatients from whom these strains were isolated were cured.Of the pneumococci two isolates, both from patients in theCXM group, appeared resistant to chloramphenicol as

judged from repeated disc-diffusion susceptibility tests. Allother strains isolated were susceptible to the three test drugs.Str. pneumoniae was more common in the CXM group, andmost patients with meningococcal meningitis were in theA+C group.The two test groups were comparable with respect to age

and sex (table I). Some of the isolates were unusual. Thepatient with Branhamella catarrhalis meningitis had chroni-

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TABLE II-BACTERIAL SPECIES ISOLATED FROM EVALUABLE PATIENTS

AND CLINICAL OUTCOME OF THE INFECTIONS

bronchitis. A skull fracture explained the meningitis causedby an a-streptococcus strain. 3 patients in each group hadclinical symptoms of otitis on admission. 3 more cases of

underlying infection, 1 each with chronic bronchitis,purulent conjunctivitis, and osteitis, were noted in the CXMgroup, in which there was also 1 case of sarcoidosis. In theA+ C group 1 patient had Arnold-Chiari syndrome and 1 hadan operated ventricular septal defect of the heart. In theremaining patients no complicating or underlying conditionswere noted.

In each of the groups 2 patients died. In the CXM group thepatients who died were a 3-year-old boy with H. influenzaemeningitis (he was unconscious at admission and respiratoryarrest developed before treatment) and an 88-year-old manwith Staphylococcus aureus meningitis originating from anosteitis and abscess which was not recognised and drained. Atnecropsy there were no signs of meningeal inflammation, butthe patient had multiple brain abscesses. In the A + C group 1child with meningococcal meningitis and 1 with H. influenzaemeningitis died. Both were in extremely poor condition onadmission. 1 patient in the CXM group and 3 in the A+ C

group were considered improved not recovered-i.e., theyhad remaining symptoms at the end of the treatment course.The CXM patient was an 80-year-old woman with H.influenzae meningitis; she had a right-sided paresis at

admission, which persisted after treatment. The 3 A+Cpatients were a patient with H. influenzae meningitis andseptic arthritis of both elbows, who recovered from themeningitis but whose arthritis relapsed and required long-term antibiotic treatment; a 2-year-old boy with meningitiscaused by H. parainfluenzae, who had persistingoculomotorius paresis at discharge from hospital; and a54-year-old woman with pneumococcal meningitis and otitis.She had complete loss of hearing in one ear and a 40 db loss inthe other at the end of treatment.At follow-up examination 6 weeks after discharge from

hospital 1 CXM patient with H. influenzae meningitis hadcomplete hearing loss in one ear and an 80 db loss in the otherAnother patient in the CXM group with H. influenzaeaetiology had a normal electroencephalogram at follow-up,but epilepsy developed 7 months later. The relation of theepilepsy to the meningitis was doubtful. 1 A+ C patient withmeningococcal meningitis recovered uneventfully but wasreadmitted with a relapse indicated by clinical signs andlaboratory analysis of CSF, but which could not be verifiedbacteriologically. In the remaining patients, 16 in the CXMgroup and 13 in the A+ C group, no sequelae were noted atfollow-up.The outcome of the infections was not related to the length

of the treatment period. In the CXM group, the mean lengthof the treatment period was 9 (range 7-14) days. 5 A+Cpatients with meningococcal meningitis were treated with thecombination for only 5 days and were cured. 2 of the otherpatients were continued on chloramphenicol alone for afurther 5 and 6 days, respectively. 12 patients were continuedon ampicillin alone for 2-11 (mean 3’ 3) further days.Repeated cultures of CSF samples taken within 48 h of the

first treatment dose were obtained from 20 evaluable patients

TABLE III-SERUM AND CSF CONCENTRATIONS OF CEFUROXIME

Children received 60-75 (mean 68) mg/kg body weight every 8 h. Adults* received 3 g every 8 h: corresponding dose/kg body weight given where known.t Treatment day 1 is the day the first dose was given.t Patient with no meningeal inflammation.S Patient with probable serous meningitis. ND = not done.

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in the CXM group and 13 in the A + C group. In all of these

patients the CSF was sterile. Repeated cultures of blood werecarried out in a few patients; blood cultures were positive24-48 h after the start of the treatment in the 2 CXM patientswho died and in the patient who received cefuroxime for apneumococcal meningitis and in whom hearing defects

developed.

Adverse Reactions

All patients were carefully observed for adverse reactions tothe test drug or drugs. Such reactions were reported on eightoccasions in 7 patients in the CXM group and in 4 patients inthe A+ C group. Rashes developed in 2 CXM patients and 3A+ C patients; this led to discontinuation of ampicillin in 1patient. Fever was noted in 2 CXM patients. Moderatelysevere diarrhoea which required symptomatic treatmentdeveloped in 1 patient in each group, and 1 CXM patient hadrepeated thrombophlebitis. With the exception of 1 patientwith an ampicillin-related rash, treatment was continued inall of the above patients. In the CXM group 1 patient lost hishair; this event was considered unrelated to cefuroxime. In 1CXM patient who had raised serum levels of alkaline

phosphatases and alanine aminotransferase on admissionthere were further increases during treatment.

CSF and Serum Concentrations

Table III gives the serum and CSF concentrations ofcefuroxime. Most samples were taken 6 h or more afteradministration of the antibiotic; the CSF concentrationsfound were high, and in most cases therapeutic levelswere maintained throughout the intervals between doses.The results could have been affected by blood contaminationin three samples of CSF (patients 616, 617, and 637). Data onerythrocytes in CSF were lacking for three other samples,which showed no signs of blood contamination. The meanCSF concentration of chloramphenicol in 14 patientssampled 1-8 (mean 4-8) h after a dose was 9-9 (range0-8-30-7) g/ml 24-48 h after the start of the treatment.

Discussion

We have made a prospective, randomised, and controlledstudy of consecutive patients with acute bacterial meningitis.Few such studies have been carried out, presumably becauseof the difficulty of obtaining adequate series of patients in areasonable time. We chose a multicentre design so we couldcomplete it in slightly over a year. We managed to include 50patients with acute purulent meningitis in the study: fourpaediatric departments, covering a population of about400 000 children below the age of 17 years, and three largeinfectious disease units participated. This patient populationrepresented the majority of patients with purulent meningitisadmitted to the participating centres during the study period:only 9 patients who fulfilled the inclusion criteria of theprotocol were not entered into the study. According to theweekly epidemiological reports from the Swedish NationalBacteriological Laboratory there were only 108 cases ofmeningococcal infection in the country during the studyperiod of about 13 months. Of these, 13 were admitted to theparticipating centres and 11 were included in the study.The results showed that cefuroxime is at least as effective as

a combination of ampicillin and chloramphenicol for thetreatment of acute bacterial meningitis caused by susceptiblepathogens. The 2 deaths in each of the treatment groupscould easily be explained by the poor condition of the patients

on admission or, in one case, by the existence of an osteitis andabscess which was not recognised and drained. Thefrequency of hearing loss, 1 in each group, was low.

Several factors emphasise the need for an alternative toampicillin, benzylpenicillin, and chloramphenicol for use inacute bacterial meningitis. Many patients are allergic topenicillins, and at present only chloramphenicol is an

alternative in these cases. The increasing frequency of

(3-lactamase-producing strains of H. influenzae has alreadypartly invalidated the use of ampicillin and other penicillinsin meningitis in the age group between 6 months and 6 years,and the few alarming reportsls°16 of meningitis caused bychloramphenicol-resistant strains of this species mean thatthe antibacterial activity of chloramphenicol can no longer beguaranteed.Cefuroxime seems to penetrate the blood-CSF barrier at

least as well as ampicillin. 17,18 In our study we found excellentCSF penetration in patients with purulent meningitis, whichseemed to result in therapeutic CSF levels for most, if not all,of the 8 h interval between two doses. All three majorpathogens causing bacterial meningitis are susceptible tocefuroxime, and there are so far no reports of resistance inH. influenzae to cefuroxime. In addition cefuroxime has abroader spectrum against gram-negative aerobic pathogensthan ampicillin,19 and because of its (3-lactamase stability it isactive against Staph. aureus, irrespective of penicillinaseproduction. With regard to cross-hypersensitivity in

penicillin-allergic patients, such a risk is likely to exist inabout 8% of patients who have reacted to penicillins.2oWhether cefuroxime is the ideal choice among the new

cephalosporins remains to be seen. Cefuroxime seems to be avaluable alternative to the traditional antibiotics for treat-ment of bacterial meningitis, especially when the pathogen isthought to be H. influerzzae. Further studies should beundertaken on the use of cefuroxime in bacterial meningitis(e.g., those caused by Enterobacteriaceae or Staph. aureus) aswell as in cases of neonatal meningitis; in treating the lattercondition it must, however, be remembered that cefuroximeis not active against Listeria monocytogenes.This study was supported by a grant from Glaxo Group Research,

Greenford, Middlesex, U.K. We thank Ms Gunborg Boden, Department ofInfectious Diseases, University of UmeS, for extensive secretarial serviceduring the study and preparation of this manuscript and Dr Christopher Jones,London, for his help in compiling the data from the first part of the study.

Correspondence should be addressed to Prof. R. Norrby, Department ofInfectious Diseases, University of Umeâ, UmeS Regional Hospital, S-90185Umed, Sweden.

REFERENCES

1. Jokipii L, Jokipii AMM. Emergence and prevalence of &bgr;-lactamase producingHaemophilus influenzae m Finland and susceptibility of 102 respiratory isolates toeight antibiotics. J Antimicrob Chemother 1980; 6: 623-31.

2. Mason EO Jr, Kaplan SL, Anderson DC, Hinds DB, Feigin RD. In vitro susceptibilityof 104 clinical isolates of Haemophilus influenzae to moxalactam (LY127935)ampicillin, chloramphenicol and ticarcillin. Antimicrob Ag Chemother 1980, 17:470-73.

3. Ward JI, Tsai TF, Filici GA, Fraser DW. Prevalence of ampicillin- and

chloramphenicol-resistant strains of Haemophilus influenzae causing meningitis andbacteremia: national survey of hospital laboratories. J Infect Dis 1978; 138: 421-24

4. Howard AJ, Hince CJ, Williams JD Antibiotic resistance in Streptococcus pneumoniaeand Haemophilus influenzae. Report of a study group on bacterial resistance. Br MedJ 1978, i: 1657-60.

5. Williams EW, Watts JA, Potten MR Streptococcus pneumoniae resistant to penicillinand chloramphenicol in the U.K Lancet 1981; ii: 699.

6. Appelbaum PC, Bhamjee A, Scragg JN, Hallet AF, Bowen AJ, Cooper RCStreptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 1977;ii: 995-97.

7. Jacobs MR, Gaspar MN, Robins-Browne RM, Koornhof HJ. Antimicrobialsusceptibility testing of pneumococci 2. Determination of optimal disc diffusiontest for detection of penicillin G resistance. J Antimicrob Chemother 1980, 6: 53-64.

8. Fisher LS, Chow AW, Yoshikawa TT, Guze LB. Cephalothin and cephaloridine fortherapy of bacterial meningitis. Ann Intern Med 1975; 82: 689-95

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9. Belohradsky BH, Bruch K, Geiss D, Kafetzis D, Marget W, Peters G. Intravenouscefotaxime in children with bacterial meningitis. Lancet 1980; i: 61-63.

10. Nair SR, Cherubin CE, Weinstein M. Penetration of cefoxitin into cerebrospinal fluidand treatment of meningitis caused by Gram-negative bacteria. Rev Infect Dis 1979;i: 134-41.

11. Renlund M, Pettay O. Pharmacokmetics and clinical efficacy of cefuroxime in thenewborn period. Proc Roy Soc Med 1977; 70 (suppl. 9): 179-82.

12. Steinberg EA, Overturf GD, Wilkins J, Baraff LJ, Strong JM, Leedom JM. Failure ofcefamandole in treatment of meningitis due to Haemophilus influenzae type b.J Infect Dis 1978; 137 (suppl.): S180-86.

13. Fisher JF, Carter MJ, Parsons J, Rissing JP. Moxalactam (LY127935) in treatment ofmeningitis due to Gram-negative bacilli. Antimicrob Ag Chemother 1981; 19:218-21

14 The Swedish Reference Group for Antibiotics. A revised system for antibiotic

sensitivity testing. Scand J Infect Dis 1981; 13: 148-52.

15. Kenny JF, Isburg CD, Michaels RH. Meningitis due to Haemophilus influenzae type bresistant to both ampicillin and chloramphenicol. Pediatrics 1980; 66: 14-16.

16. Kinmonth A, Storrs CN, Mitchell RG. Meningitis due to chloramphenicol resistantHaemophilus influenzae type b. Br Med J 1978; i: 694.

17. Hoffstedt B, Johansson Ö, Walder M, Cronberg S, Price JD. Cerebrospinal fluidpenetration of cefuroxime. In: Nelson JD, Grassi C, eds. Current chemotherapy andinfectious disease. Washington DC: American Society of Microbiology, 1980:534-35.

18. Müller C, Netland A, Andrew E. The penetration of cefuroxime into the cerebrospinalfluid through inflamed and non-inflamed meninges. J Antimicrob Chemother 1980;6: 279-83.

19. Greenwood D, Pearson NJ, O’Grady F. Cefuroxime: a new cephalosporin antibioticwith enhanced stability to enterobacterial &bgr;-lactamases. J Antimicrob Chemother1976; 2: 337-43.

20. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a

review. J Infect Dis 1978; 137 (suppl.): S74-80.

SINGLE-DOSE SLOW-RELEASEAMINOPHYLLINE AT NIGHT

PREVENTS NOCTURNAL ASTHMA

P. J. BARNESLOUISE NEVILLE

A. P. GREENING

JOSÉ TIMMERSG. W. POOLE

Respiratory Division, Department of Medicine,Hammersmith Hospital, London W12 0HS

Summary Twelve asthmatic patients with nocturnalwheezing were given a single nocturnal

oral dose of slow-release aminophylline or matched placeboin a double-blind crossover trial. A dose of slow-release

aminophylline (mean 683 mg; 10·4 mg/kg) gave a therapeuticplasma-theophylline concentration 10 h later (mean 10·9

mg/l). This was not associated with any adverse effects. Meanpeak expiratory flow on waking was significantly greater withaminophylline (332±31 1/min) than placebo (283±32 1/min),whereas evening values did not differ. There was a significantdifference between morning and evening peak flow onplacebo (mean 22%) but not on aminophylline (5%), indicat-ing abolition of the morning fall in peak flow. This was not atthe expense of response to &bgr;-agonists, since the response toinhaled salbutamol was the same for both treatments. The useof extra metered doses of inhaled &bgr;-agonist during the nightwas significantly less with aminophylline, and there was asubjective improvement in nocturnal symptoms in all

patients. Slow-release aminophylline in adequate dosageappears to be the most effective treatment yet demonstratedfor nocturnal asthma.

Introduction

WHEEZING at night is a very common, troublesome

symptom of asthma, and present treatment is unsatisfactory.The precise mechanism of increased bronchoconstriction atnight remains unclear, and it is likely that there is a

coincidence of several factors. I The circadian fall in

circulating adrenaline at night may encourage the release ofmast-cell mediators in asthmatics,2 and increased

parasympathetic activity may have a direct action on

bronchial smooth muscle. Both (3-adrenoceptor agonists andtheophyllines should prevent nocturnal asthma by a directaction on bronchial smooth muscle and by inhibiting therelease of bronchoconstrictor mediators. As neither inhalednor oral 0-agonists have a sufficiently long-lasting action toprevent nocturnal asthma, a slow-release oral preparation ofsalbutamol is commonly prescribed. However, slow-releasesalbutamol has been found to be beneficial in less than a thirdof patients, despite therapeutic plasma concentrations

overnight. Although this might indicate impaired airway&bgr;-receptor function at night, there is no evidence for circadianvariation in (3-adrenergic responsiveness in asthmatics

(Barnes PJ, Fitzgerald G, Dollery CT, unpublished). Oraltheophyllines have a short and variable plasma half-life, but aslow-release aminophylline preparation (’Phyllocontin’,Napp Laboratories) gives satisfactory and reliable plasmalevels of theophylline up to 12 h after ingestion.4 Thetherapeutic effect of theophyllines is directly related to

plasma concentration,s and now that reliable assays for

plasma theophylline are widely available it is possible todetermine whether dosage is adequate. In previous studies onadults6,7 and children slow-release aminophylline has beenshown to improve early-morning wheeze in a proportion ofasthmatics, but since plasma-theophylline concentrationswere not measured it is not certain whether a poor responsewas due to inadequate dosage.The aim of our study was to examine the effect on nocturnal

asthma of slow-release aminophylline given in a single night-time dose which was adequate to maintain therapeuticallyeffective plasma-theophylline concentrations overnight.

Patients and Methods

Patients

Twelve asthmatic patients (seven men, five women), aged 22 to 72years (mean 42), who attended the chest clinic, HammersmithHospital, were studied (see table). All experienced nocturnalwheeze or chest tightness and had airway reversibility (greater than20% increases in forced expiratory volume in one second afterinhaled 0-agonist). Nine patients had multiple positive immediateskin-prick tests to common allergens. All regularly inhaled

(3-agonists and five regularly inhaled beclomethasone; none wastaking oral 0-agonists or theophyllines or had received oral steroidswithin 4 weeks of the study. During the trial no change was made inregular medication. No patient had liver or heart disease; one (no.11) was a cigarette smoker. (A 13th patient was initially included inthe study but later excluded when it was found that she was taking atheophylline-containing preparation.) The study was approved bythe research ethics committee, Hammersmith Hospital, and allpatients gave their informed consent.

Study DesignThe dose of slow-release aminophylline necessary to give

overnight plasma-theophylline concentrations in the therapeuticrange was determined in an open phase before the trial: plasma-theophylline concentration was measured at 4 - 6 h (peak) and thenat 10 h after a single oral dose. The dose was adjusted if necessary togive a plasma-theophylline concentration at 10 h of approximately10 mg/1. Plasma-theophylline concentration was determined withhigh-pressure liquid chromatography.9 All patients had previousexperience of recording peak expiratory flow (PEF) at home.