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CEFTAZIDIME FOR PSEUDOMONAS MENINGITIS

SIR,-Dr Alestig and colleagues report (Jan 19, p 161) successfultreatment of meningitis due to Pseudomonas aeruginosa withceftazidime as the sole agent. We would re-emphasise the

importance of monitoring the sensitivity of bacteria isolated duringtherapy with this agent since we have encountered resistanceemerging during treatment in two patients with infections at othersites.A 35-year-old man with multiple injuries sustained in an

industrial accident abroad was transferred to this hospital 2 weeksafter injury. Bacteroides fragilis was isolated from blood culturestaken on admission and B fragilis and Proteus morganii from pus inthe left tibia. Treatment was intravenous ceftazidime 1 g 8-hourly,netilmicin 100 mg 8-hourly, and metronidazole 400 mg 12-hourly.Swabs taken from the leg wound 8 days later yielded P morganii andPs aeruginosa. The pseudomonas was sensitive to ceftazidime at thisstage, the minimum inhibitory concentration (MIC) being 1-2jg/ml by agar dilutions. Swabs from the same site taken 3 days latergrew B fragilis, P morganii, Streptococcusfaecalis, and Ps aeruginosa(MIC 16-31 g/ml), the pseudomonas being of the same serotype(011) was the earlier isolate.The second patient was a 58-year-old man with lower cranial

nerve damage after removal of an acoustic neuroma and aspirationpneumonia. Because Serratia marcescens and Enterobacter cloacaehad been isolated from blood cultures taken before removal of aninfected intravenous feeding cannula 4 days previously therapy wasstarted with ceftazidime 1 g 8-hourly, metronidazole 400 mg12-hourly, and gentamicin 80 mg 8-hourly. Ps aeruginosa (MIC8-13 fg/ml), Klebsiella aerogenes, and group B streptococcus wereisolated from sputum. 5 days after the start of antibiotic therapy thepatient became pyrexial again and deteriorated clinically. The tip ofan intravenous line was removed from which Ps aeruginosa, nowresistant to ceftazidime (MIC 62-250 lAg/ml) was isolated. A bloodculture taken at this time yielded a coagulase negativestaphylococcus, S marcescens and Strfaecalis. The patient improvedafter removal of the infected cannula, antimicrobial therapy beingcontinued for a further 4 days.The serotypes of the isolates from the first patient were identical;

the strains from the second patient were non-typable but similarusing the new API system for non-fermenters. Hence it would seemthat we were not dealing with new infections and that in bothpatients the original strains persisted despite chemotherapy. Thesecond "resistant" isolate of Ps aeruginosa from each patient showedan 8-16 fold increase in MIC compared with the "sensitive"strains. The strains have been examined by isoelectric focusing andthe mechanism of resistance appeared to be due to excessive

production of chromosomally mediated P-lactamase. 1,2In our patients resistance to ceftazidime emerged despite

concurrent aminoglycoside therapy. Since those receiving agentssuch as ceftazidime are, by nature of their underlying medicalconditions, likely to be long-term hospital patients, the emergenceof organisms showing wide cross-resistance to most second andthird generation cephalosporins and broad spectrum penicillinsmay have implications for other patients should cross-infectionoccur. Hence we conclude that use of new cephalosporins should bemonitored closely for the sake both of the individual patient and ofthe population at large.We thank Miss Anne Harris of Glaxo Ltd for the isoelectric focusing studies.

Department of Microbiology,Newcastle General Hospital,Newcastle upon Tyne NE4 6BE

S. J. HUDSONH. R. INGHAM

1 Sanders CC, Sanders WE. Emergence of resistance during therapy with the newer&bgr;-lactamase antibiotics: Role of inducible &bgr;-lactamase and implications for thefuture. Rev Infect Dis 1983; 5: 639-48

2 Sanders CC. Novel resistance selected by the new expanded spectrum cephalosporins: aconcern. J Infect Dis 1983, 147: 585-89.

SlR,—Dr Alestig and colleagues reported the successful treatmentof a single case of Pseudomonas meningitis with ceftazidime. Thiswas one of the earliest cases reported to us but there have been otherpublished cases 1-3 besides the 3 Alestig et al refer to. We havereceived full reports of 28 cases in clinical trials and treated under an

emergency protocol, and a further 7 successful treatments werereported by Concia et al at a recent conference.4

4

In 17 of these 35 cases ceftazidime was given in combination withan intravenous aminoglycoside to treat infections, 12 of which hadnot responded to an aminoglycoside alone or in combination withanother &bgr;-Iactam. 3 of these 17 patients died: 1 was a baby, anotherwas in a coma having not responded to azlocillin plus tobramycin,and a third died of a neuroma and secondary haemorrhagepostoperatively but had sterile CSF at necropsy. The remaining 14patients responded.Of the other 18 patients (including Alestig’s) 16 were given

ceftazidime alone and the other 2 had vancomycin or metronidazoleas well. All were successfully treated.

10 of the 28 cases reported in detail were less than three years old,including 6 less than two months. These younger patients hadhydrocephalus, burns, spina bifida, or congenital heart disease. 1

patient with necrotising enterocolitis was the only patient in theseries for whom a pre-treatment CSF sample was not obtained. Thispatient had clinical signs of meningitis and Pseudomonas was grownfrom the faeces.The adults usually had infections after surgery for neuroma or

otitis media or had multiple injuries as the result of road-trafficaccidents. 3 patients had brain abscesses and 1 patient had aplasticanaemia.Adults were usually treated with ceftazidime 2 g 8-hourly

although five had doses of 8-9 g/day and 1 patient received 4 g8-hourly. The duration of treatment was 4, 6, and 11 days in thethree patients who died and from 10 to 85 days (mean 2 days) in thesurvivors. All patients received ceftazidime intravenously but 3 alsohad intraventricular administration, the doses being 50 mg every48 h, 25 mg every 72 h, and 250 mg every 48 h. The 250 mg dose wasprobably excessive but it was well tolerated. The dosage in infantswas 100-150 mg/kg daily except in 3 cases given daily doses of 50mg/kg (1 patient) or 300 mg/kg (2 patients).There was a single case of Ps cepacia and one of Psfluorescens, both

of which responded to ceftazidime monotherapy. The remainingstrains were Ps aeruginosa or were not specified. Minimal inhibitoryconcentrations (MIC) were reported for 14 strains; 13 MICs werebelow 4 mg/1. One strain with a reported MIC of 31 2 mg/1 waseradicated by 2 g 6-hourly ceftazidime intravenously combined withtobramycin intravenously and also intrathecally at a dose of 7 mg. 4patients received aminoglycosides by this route.The clinical success in 32 of 35 patients reflects the activity of

ceftazidime against Pseudomonas and good penetration throughinflamed meninges, as reported by Alestig et al and by others.5.?

We thank the clinicians who submitted case-reports.

Medical Division,Glaxo Group Research Ltd,Greenford, Middlesex UB6 0HE

K. J. WILLIAMSR. D. FOORD

1. Daikos GK, Kosmidis J, Stakathis H, Giamarellou H, Douzinas E, Kastanakis S,Papathanassion B Ceftazidime therapeutic results in various infections and

therapeutic studies J Antimicrob Chemother 1981, suppl B; 331-38.2 Modai J, Meulemans A, Vittecoq D Treatment of Pseudomonas aeruginosa meningitis

with ceftazidime. J Antimicrob Chemother 1983, 11: 198-99.3 Modai J, Vittecoq D, Acar J, Rey J. Use of ceftazidime in bacterial meningitis In:

Proceedings of 13th International Chemotherapy Conference (Vienna, 1983); 101:43-45

4. Concia E, Ugazio AG, Carbonera D, Dionigi R. Open study of the efficacy, safety andtolerability of ceftazidime in the treatment of serious bacterial infections In: Ilceftazidimi (Glaxo Italy conference proceedings): 131.

5. Modai J, Vittecoq D, Decazes JM, Wolff M, Meulemans A Penetration of ceftazidimeinto cerebrospinal fluid of patients with bacterial meningitis Antimicrob AgChemother 1983; 12: 126-28

6. Fong IW, Tomkins KB. Penetration of ceftazidime into the cerebrospinal fluid ofpatients with and without evidence of meningeal inflammation. Antimicrob AgChemother 1984; 26: 115-16.

7. Romero-Vivas J, Martinez-Beltran J. Hellin T, Guerrers A, Loza E Bouza E. InProceedings of 13th International Chemotherapy Conference (Vienna, 1983); 101:47-51

RISING INCIDENCE OF ECZEMA

SIR,-The findings of Mr Peters and his colleagues (Jan 5, p 49)are broadly in accord with ours,l pointing to a substantial rise inreported eczema since the 1940s not primarily related to the contem-

465

poraneous reduction in breastfeeding. We chose the variables forour analysis to permit comparison between the cohorts, andparental education was not available in all three cohort studies. Weare surprised that’Peters et al did not include maternal eczema as apredictive factor for childhood eczema. Despite differences stem-ming from different hypothetical approaches, we hope that ourpaper on the prevalence of childhood eczema has demonstrated thevalue of cohort studies in the investigation of changes in illnessprevalence and medical practice over the first 29 years of theNational Health Service.

Departments of Paediatricsand Community Medicine,

St Mary’s Hospital Medical School,London W2 1PG

BRENT TAYLOR

JANE WADSWORTHMRC National Surveyof Health and Development,

University of Bristol M. E. J. WADSWORTH

Department of Community Medicineand General Practice,

Charing Cross HospitalMedical School,

London W6 CATHERINE S. PECKHAM

1 Taylor B, Wadsworth J, Wadsworth MEJ, Peckham CS. The changing prevalence ofreported eczema in Great Britain since the 1939-45 war Lancet 1984, ii: 1255-57.

LACTOSE MALABSORPTION

SIR,-Surely Dr Brasseur and colleagues (Jan 12, p 100) aregetting themselves into an unnecessary muddle over the term"lactose malabsorption". Malabsorption of lactose is caused byprimary lactase deficiency (low brush border lactase activity andnormal small-intestinal morphology), secondary lactase deficiency(low brush border lactase activity secondary to small-intestinalmucosal damage), or, very rarely, congenital lactase deficiency.Their children clearly have small-intestinal mucosal damage and

secondary lactase deficiency so their results are entirely predictable.In small-intestinal mucosal damage (eg, in coeliac disease) brushborder disacchandase activities, especially lactase, are decreased 1-3and intact dietary disaccharide such as lactose is excreted

unchanged in the urine. This absorption of unhydrolysed lactosein secondary lactase deficiency is the result of increased passivepermeability of the small intestine to small hydrophilic molecules(eg, disaccharides) as a consequence of the mucosal damage. Inuntreated coeliac disease, small-intestinal permeability to thedisaccharides cellobiose and lactulose5.6 is increased; similarly,permeability to lactulose is increased m tropical enteropathy.7Children with primary lactase deficiency, who cannot hydrolyse

dietary lactose or absorb significant amounts of intact lactose, andBrasseur’s children with secondary lactase deficiency, who cannothydrolyse lactose but can absorb some intact lactose (although it isexcreted unchanged and is not metabolised) both have

malabsorption of lactose in that dietary lactose cannot be absorbedin metabolisable form. Therefore lactose malabsorption is a

perfectly useful term for these situations of "bad" absorption;however, it is important to recognise that the term does not indicatethe pathological mechanisms that may be involved.

Department of Medicine,Bristol Royal Infirmary,Bristol BS2 8HW B. T. COOPER

1 Shmerling DH, Auricchio S, Rubino A, Hadorn B, Prader A. Der sekundare Mangel anintestinaler Disaccharidasaktivitat bei der Coeliakie; quantitative Bestimmung derEnzymaktivitat und klinische Beurteilung. Helv Paediatr Acta 1964, 19: 507-27.

2. Weser E, Sleisenger MH Lactosuria and lactase deficiency m adult coliac disease.Gastroenterology 1965; 48: 571-78.

3. Pena AS, Truelove SC, Whitehead R Disaccharidase activity and jejunal morphologyin coeliac disease Quart J Med 1972: 41: 457-76.

4. Cobben I, Dickinson RJ, Rothwell J, Axon ATR. Intestinal permeability assessed byexcretion ratios of two molecules: Results in coeliac disease. Br Med J 1978; ii: 1060.

5. Menzies IS, Laker MF, Pounder RE, Bull J, Heyer S, Wheeler PG, Creamer B.Abnormal intestinal permeability to sugars in villous atrophy Lancet 1979, ii:

1107-096 Ukabam SO, Cooper BT Small intestinal permeability to mannitol, lactulose and PEG

400. Dig Dis Sci 1984, 29: 809-16.7 Ukabam SO, Homeida MA, Cooper BT. Small intestinal permeability in normal

Sudanese subjects Trans Roy Soc Trop Med Hyg (in press).

DIETARY PROTEIN RESTRICTION IN CHRONICRENAL FAILURE

SIR,-We would like to support Dr Westberg’s criticisms (Jan 12,p 102) of Dr Rosman and colleagues’ paper (Dec 8, p 1291). Incontrast to Rosman et al, who conclude that a low-protein diet slowsthe progression of chronic renal failure, we believe that this large,well-designed study demonstrates no relevant benefit from proteinrestriction.Rosman’s conclusions were based on creatinine levels but serum

creatinine is an inadequate index of glomerular filtration rate,unless creatinine excretion is constant, which it was not. Moreover,it seems odd to construct "survival curves" with "death" equatedwith a 1007o increase in serum creatinine (fig 2 of Rosman et al).

CREATININE CLEARANCE’ OF FOUR STUDY GROUPS VERSUS TIME

*Compured from creatinine excretion and regression equations for 1000/creatinine, aspublished by Rosman et al. Groups A and A2 had an unrestricted diet, groups B and Creceived 0-6g and 0’4g protetn/kg/d, respectively.

We have used their data on urinary creatinine excretion togetherwith the regression equations for 1000/creatinine to compute meancreatinine clearances (table). The patients with moderate renalfailure (groups A and B) did not benefit in any way from proteinrestriction; their creatinine clearance remained essentially constantover the 18 month observation period. In contrast, both patientgroups with more advanced renal failure (groups A2 and C) showeda progressive loss of creatinine clearance, which was only slightlygreater in the protein-restricted group (3’ 7 vs 4’ 8 ml/min). Hence,the differences in the evolution of serum creatinine may largely beaccounted for by differences in creatinine excretion, whichincreased in group AI, remained stable in groups B and A2, anddecreased in group C. We doubt Rosman and colleagues’explanation that the decrease in creatinine excretion in the protein-restricted group C was merely due to diminished intake of meatbecause the steady downward trend, present at 3 months, continuedat 9 and 18 months. More probably this represents decreasingendogenous creatinine production caused by progressive loss ofmuscle mass. This study seems to confirm F. Parsons’ saying that"all a low protein diet does is to shrink the patient down to the size ofhis kidneys".Division of Nephrology,Kantonsspital,4000 Basel, Switzerland

H. A. BOCKF. P. BRUNNER

SIR,-We appreciate the comments of your Jan 12 (p 102)correspondents and others on our article on dietary proteinrestriction in chronic renal failure.’ Data on the diagnostic groupsreceiving most benefit will soon be available; preliminary dataaccord with Dr Williams and colleagues’ findings. ’In response to Dr Westberg, we acknowledge the superiority of

the glomerular filtration rate (GFR) as an indicator of progression ofrenal functional deterioration. To compare our results with

previous investigations, however, we used reciprocal serum

creatinine values. Regression analyses on the patterns of creatinineclearance were done as well (see figure).Creatinine clearance fell significantly in all four groups during

the follow-up of 18 months (A 1 p<0 - 05; B p<0 - 05; A2 p<0 - 001; C

’ p<0-01), but we found striking differences between the slopes infavour of the protein-restricted groups (A vs B p<0-005; A2 vs C

p<0 02). The median losses of creatinine clearance per year were3-5 (Al), 1-6 (B), 4-2 (A2), and 2-3 (C7) ml per min per 1-73 m2.Thus the slower increase of serum creatinine in the groups on a

protein-restricted diet seems not to be due to a decreased creatinine