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data suggest that the reported cluster of isolations of VRE wasdue to a single nosocomial strain of Efaecalis.A major obstacle in prophylactic SDD is the possible

overgrowth of microorganisms resistant to the antibiotics

used.s In particular, outbreaks due to MRSA6 and Efaecalis7have been associated with the use of SDD. In our cluster, theroutine application of SDD for extended periods to all

inpatients in the intensive care unit may have favoured anoutbreak of infections due to MRSA, and the subsequentemergence of VRE in those treated with glycopeptides forMRSA infection. Thus, VRE and MRSA could be two links inthe same chain, with SDD being a fundamental contributingfactor.

Esther Manso, Giuseppina De SioDiagnostic Laboratory, Department of Bacteriology, Torrette Regional Hospital,60020 Ancona, Italy

Francesca Biavasco, Pietro E VaraldoInstitute of Microbiology, University of Ancona Medical School

Gisella SamboIntensive Care Unit, Department of Anaesthesia, Torrete Regional Hospital

Claudio Maffei

Hospital Infection Control Service, Torrette Regional Hospital

1 Spera RV Jr, Farber BF. Multiply-resistant Enterococcus faecium: thenosocomial pathogen of the 1990s. JAMA 1992; 268: 2563-64.

2 Leclercq R, Dutka-Malen S, Brisson-Noël A, et al. Resistance ofenterococci to aminoglycosides and glycopeptides. Clin Infect Dis 1992;15: 495-501.

3 Maki DG, Weise CE, Sarafini HW. A semi-quantitative culturemethod for identifying intravenous catheter-related infection. N Engl JMed 1977; 296: 1305-09.

4 Rhinehart E, Smith NE, Wennersten C, et al. Rapid dissemination of&bgr;-lactamase-producing, amino-glycoside-resistant Enterococcus faecalisamong patients and staff on an infant-toddler surgical ward. N Engl JMed 1990; 323: 1814-18.

5 Hammond JM, Potgieter PD, Saunders GL, Forder AA. Double-blindstudy of selective decontamination of the digestive tract in intensivecare. Lancet 1992; 340: 5-9.

6 Kaufhold A, Behrendt W, Kräuss T, van Saene H. Selectivedecontamination of the digestive tract and methicillin-resistantStaphylococcus aureus. Lancet 1992; 339: 1411-12.

7 Bonten MJM, van Tiel FH, van der Geest, Stobberingh EE,Gaillard CA. Enterococcus faecalis pneumonia complicating topicalantimicrobial prophylaxis. N Engl J Med 1993; 328: 209-10.

Pentoxifylline and wellbeing in cancer

SIR—The pluripotent cytokine tumour necrosis factor-alpha(TNFx) plays a part in the mediation of fatal sepsis and theadult respiratory distress syndrome, and has been implicated inthe pathogenesis of cancer cachexia.1 Dezube and colleagueshave reported improvement in wellbeing of people with cancertaking pentoxifylline, and suggested that it may be secondary toTNAa inhibition.2 We assessed the quality of life and fatiguestatus of people with cancer taking pentoxifylline as part of alarger study.

Subjects with gastrointestinal cancer were enrolled in a2-week randomised double-blinded placebo-controlled studyof pentoxifylline 400 mg three times a day. Assessments ofquality of life and fatigue were carried out before and after the2-week study period. Quality of life was assessed with thefunctional living index-cancer (FLIC) questionnaire,3 andfatigue status by a self-administered Otago University fatiguequestionnaire (OUFQ).4

12 people with advanced, mainly colorectal, cancer werestudied. 6 subjects were randomised to each arm, there beingno significant differences in basal demographic features. Nosignificant changes were found within and between the placeboor pentoxifylline groups for each test of wellbeing. Our study,

with a dose of pentoxifylline known to cause TNFa inhibition,does not confirm an improvement in wellbeing or reduction infatigue, and raises doubts about TNFa as the sole mediator ofcancer cachexia.

J A Tuckey, B R Parry, J L McCall6 Fiona Place, Hamilton, New Zealand

1 McCall JL, Parry BR. Tumour necrosis factor in surgical illness. AustN Z J Surg 1990; 60: 503-09.

2 Dezube BJ, Fridovich-Keil JL, Bouvard I, et al. Pentoxifylline andwellbeing in patients with cancer. Lancet 1990; 335: 662.

3 Schipper H, Clinch J, McMurray A, et al. Measuring the quality of lifeof cancer patients: the Functional Living Index-Cancer: developmentand validation. J Clin Oncol 1984; 2: 472-83.

4 Buxton LS, Frizelle FA, Hopkins WG, et al. Validation of subjectivemeasures of change in fatigue following surgery. Eur J Surg 1992; 158:393-36.

Tight glucose control and diabeticcomplicationsSiR-The preliminary results of the Diabetes Control andComplications Trial (DCCT) have provided incontrovertibleevidence ’of the importance of good glycaemic control toimpede the development of diabetic microangiopathy. Thisoutcome is welcome but comes as no surprise to most diabetesspecialists in Europe who have accepted for many years theevidence of Pirart1 and others2-5 about the relation between

good glycaemic control and diabetic complications. In yourotherwise well-balanced July 17 commentary on the

implications of the DCCT results, Wang makes the surprisingcomment that "a good meta-analysis is an excellent alternativeto a large multicentre trial". The meta-analysis by Wang andcolleagues6 arrived at conclusions similar to those of the

DCCT. However, the potential impact of these alternativescientific approaches on clinical practice is likely to be quitedifferent.The selectivity and inherent risks of overinterpretation of

meta-analysis are well recognised and Wang et al6 make justsuch an overinterpretation when they state "with reasonablecontrol patients in most studies included were at low risk ofdeveloping proliferative retinopathy. The protective effect ofintensive therapy may be greater with higher levels of

glycaemic control". Although it is axiomatic that diabetic

patients with the poorest glycaemic control have most togain from its improvement, one of the key findings of theDCCT is the absence of a threshold effect of blood glucose-ie, no level of hyperglycaemia is safe. On the contrary, a linearrelation has been shown to exist between glycatedhaemoglobin concentration and the frequency of micro-vascular disease.The role of glycaemic control was investigated in the Steno,2 2

Kroc,3 Oslo,4 and Stockholms studies, all of which were fairlysmall prospective trials and were included in the meta-

analysis.6 Wang et al6 drew attention to the significantdifferences in incidence of hypoglycaemia reported in some ofthese studies, despite achieving similar levels of glycaemiccontrol. However, this discrepancy can be explained by theapplication of different definitions of hypoglycaemia. Forexample, in the Steno study,2 hypoglycaemia was defined onthe basis of a blood glucose concentration below 25 mmol/L,and this biochemical hypoglycaemia was not necessarilysymptomatic. By contrast, in the Stockholm study5 data wereobtained about severe hypoglycaemia (episodes requiringexternal help to facilitate recovery), which was more commonin the intensively treated group. Wang’s6 conclusion that thedifferent incidences of hypoglycaemia cannot be explained bythe quality of glycaemic control is erroneous because differentdefinitions of hypoglycaemia were used in the two studies. In

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conducting a meta-analysis it is important that like is comparedwith like.

Although there may be a place for a careful meta-analysis ofclinical trials, this approach cannot replace large scale

prospective studies such as the DCCT. Moreover, to suggestthat the results of a meta-analysis should be given the samescientific weight is surely to greatly overstate the case. TheDCCT was a prospective clinical study that was conductedwith great care. The study was designed to provide a definitiveanswer to whether good glycaemic control protects the

microvasculature, and the preliminary results have providedthe most robust evidence for this yet available. The DCCT willhave a major impact in strengthening the case for the necessaryresources to deliver an appropriate quality of diabetic care,thereby improving the long-term prognosis and reducing themorbidity associated with diabetes.

Kenneth M MacLeod, Ann E Gold, Brian M FrierDepartment of Diabetes, Royal Infirmary of Edinburgh and Associated Hospitals,Edinburgh EH3 9YW, UK

1 Pirart J. Diabetes mellitus and its degenerative complications: aprospective study of 4400 patients observed between 1947 and 1973.Diabetes Care 1978; 1: 168-88; 262-63.

2 Lauritzen T, Larsen HW, Deckert T, Steno Study Group. Two yearsexperience with continuous subcutaneous insulin infusion in relationto retinopathy and neuropathy. Diabetes 1985; 34 (suppl 3): 74-79.

3 The Kroc Collaborative Study Group. Diabetic retinopathy after twoyears of intensified insulin treatment. JAMA 1988; 260: 37-41.

4 Brinchmann-Hansen O, Dahl-Jorgensen K, Sandrik L, Hanssen KF.Blood glucose concentrations and progression of diabetic retinopathy:the seven years results of the Oslo Study. BMJ 1992; 304: 19-22.

5 Reichard P, Berglund B, Britz A, Cars I, Nilsson BY, Rosenqvist U.Intensified conventional insulin retards the microvascular

complications of insulin-dependent diabetes (IDDM): the StockholmDiabetes Intervention Study (SDIS) after 5 years. J Intern Med 1991;230: 101-08.

6 Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensiveblood-glucose control on late complications of type 1 diabetes. Lancet1993; 341: 1306-09.

Authors’reply

SiR-MacLeod and colleagues raise a frequently asked

question about meta-analysis: how should we compare ameta-analysis to a large multicentre trial? Meta-analysis is ayoung discipline of clinical research; the method itself isundergoing continuous development, and the comparisonbetween meta-analysis and large multicentre trial remains to bedefmed. Although the large randomised controlled trial may bea good gold standard against which to test a clinical hypothesis,meta-analyses have been shown to provide close approximationof the results of large trials.1 Thus, a meta-analysis can be agood alternative to a large trial. MacLeod and colleagues mighthave misunderstood our articles because we have never claimed

that meta-analyses are equal to large trials or that our

meta-analysis may replace the DCCT. The massive DCCTrepresents the efforts from many well-regarded investigators;our meta-analysis represents a summarised conclusion fromsmaller randomised studies published before the DCCT. Thesimilarities in conclusions independently reached by themeta-analysis and the DCCT further confirm the protectiveeffects of intensive therapy on diabetic complications.Our speculation that the protective effect of intensive

therapy may be greater in patients with poor glycaemic controlis based largely on data gathered from epidemiological studies.Patients with higher glycosylated haemoglobin have a higherfrequency of microangiopathy. There are no reliable datasuggesting that the effect of intensive therapy is the same or lessin patients with higher glycosylated haemoglobin. Like ourmeta-analysis, the DCCT was not designed to test the effect ofglycaemia threshold on diabetes complications.

The frequency of severe hypoglycaemia in the Steno studywas estimated according to the criteria outlined in our

investigation.2,3 Although hypoglycaemia was defmed as

glucose below 25 mmol/L in the Steno study, the occurrence ofsevere hypoglycaemia was also reported in that study.4 Onlythe data on severe hypoglycaemia, not hypoglycaemia, wereincluded in our analysis. Therefore, the way we integrate andinterpret the incidence of severe hypoglycaemia is logicallybased on both the original data and the analysis.

Ping H Wang, Joseph Lau, Thomas C ChalmersJoslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA

1 Antman EM, Lau J, Jimenez-Silva J, Kupelnick B, Mosteller F,Chalmers TC. A comparison of results of meta-analyses of randomizedcontrol trials and recommendations of clinical experts: treatments for

myocardial infarction. JAMA 1992; 268: 240-48.2 Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive

blood-glucose control on late complication of type 1 diabetes. Lancet1993; 341: 1306-09

3 Wang PH, Lau J, Chalmers TC. Metaanalysis of the effects ofintensive glycemic control on late complications of type 1 diabetesmellitus. Online J Curr Clin Trials 1993; May 21: doc no 60

4 Feldt-Rasmussen B, Mathiesen SR, Deckert T. Effect of two years ofstrict metabolic control on progression of incipient nephropathy ininsulin-dependent diabetes. Lancet 1986; ii: 1300-04

Negligible excretion of 5-aminosalicylic acidin breast milk

SIR—Sulphasalazine (SZ) and its metabolite 5-aminosalicylicacid (5-ASA) are drugs of first choice for the treatment ofchronic inflammatory bowel disease. Published reports showthat SZ crosses the placenta, but only small amounts areexcreted in breast milk.1 In a woman with ulcerative colitis

(UC) who was taking 500 mg 5-ASA thrice daily, singlesamples of blood and breast milk taken 5 25 h after the last oraldose indicated a milk/plasma ratio of027 for 5-ASA and of 5 1for its acetylated major metabolite (Ac-5-ASA).2 One casereport described a 25-year-old mother with UC treated with5-ASA rectally (500 mg twice daily). Her breast-fed infantdeveloped watery diarrhoea 12 h after the first dose.

Rechallenge trials indicated that excretion of 5-ASA in breastmilk might have caused this side-effect. 3We investigated a 29-year-old woman with inactive UC (1 g

5-ASA thrice daily), and measured how much 5-ASA andAc-5-ASA was excreted in breast milk and taken up by hernewborn infant (4050 g, 52 cm). At delivery (33 h after the lastdose), 5-ASA/Ac-5ASA concentrations (high-performanceliquid chromatography) were 0-4/57 )J.g/mL in the umbilicalcord serum, whereas the maternal concentrations were 12/28ug/mL. The first maternal serum and breast-milk sampleswere taken 1 week after delivery (5 h after the last dose), thesecond set of samples 4 days later (5 h after the last dose). Bydifferential weighing the intake of milk by the baby at thosetimes was 200 and 120 mL, respectively. The followingconcentrations ([tg/mL) were measured:

Based on the milk intake and its low content of 5-ASA, a dailyoral infant dose of about 0 065 mg 5-ASA (or 0 015 mg/kg)could be calculated (adult dosage range is 20-40 mg/kg).Higher but still negligible amounts of the inactive metabolitewould be absorbed by the baby (approximately 10 mg per dayor 2 3 mg/kg). We have previously found low drug levels in theplasma (0-9 ug 5-ASA/mL; 2-1 ug Ac-5-ASA/mL) and breast