1004

blinded matched placebo were both provided by Galen Pharma.Both the patient and the investigator who evaluated outcome wereunaware of the treatment assignment. A thin layer of cream was to beapplied three times a day (morning, midday, and night). The patientrecorded in a diary the duration of pain, number and type ofconcomitant analgesics used, and adverse effects. Severity of painwas evaluated by use of a visual analogue scale ranging from "no painat all" (0 min) to "the most pain I can possibly imagine" (100 min).The mean (SD) pain severity score was 10-6 (4-9) for the run-in

period, 10-7 (8-6) for the first placebo period, 18-1 (11-7) for thecapsaicin period, and 14 1 (52) for the second placebo period. Thepain was significantly worse during capsaicin treatment (p = 0 002,two-way ANOVA). Pain duration and concomitant analgesic usedid not change during the three treatment periods. Mild localadverse effects were present intermittently throughout the placeboperiods-itching and rash in the first, and prickly sensation in thesecond. During the capsaicin phase, the patient never applied thefull dose because of continual severe burning.

Capsaicin has been suggested as a local pain reliever in diabeticneuropathy,3 post-herpetic neuralgia,4 post-mastectomy painsyndrome and post-amputation stump pain.’ Unlike the patientreported previously,’ the one we describe did not benefit fromtreatment. Individual differences between our patient and the casereported previously may have contributed to our failure to

demonstrate efficacy. The dose we prescribed was three timeshigher than that used successfully before. Local adverse effects mayhave prevented our patient from applying enough medication todesensitise the skin and benefit receptors. The "N-of-l" studydesign may not be useful in assessing a medication like capsaicin,which has a delayed onset and continued effect after cessation oftherapy. We had hoped to overcome these problems with the"A-B-A" treatment sequence. More studies will be necessary todefine what types of patients might benefit from capsaicin.

Department of Communityand Preventive Medicine,

University of Rochester,School of Medicine and Dentistry,Rochester, New York 14642, USA

MICHAEL WEINTRAUBAHUVA GOLIKANA RUBIO

1. Rayner HC, Atkins RC, Westerman RA. Relief of local stump pain by capsaicin cream.Lancet 1989; ii: 1276-77.

2. Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. Then-of-1 randomized controlled trial: clinical usefulness: our three-year experience.Ann Intern Med 1990; 112: 293-99

3. Chad DA, Aronin N, Lundstrom R, et al. Treatment of painful diabetic neuropathywith topical capsaicin: a double blind multicenter investigation. American DiabeticAssociation Meeting, June 3-6, 1989; abstr

4. Bernstein JE, Bickers DR, Dahl MV, Roshal JY. Treatment of chronic postherpeticneuralgia with topical capsaicin. A preliminary study J Am Acad Dermatol 1987;17: 93-96.

5. Watson CPN, Evans RJ, Watt VR. The postmastectomy pain syndrome and the effectof topical capsaicin. Pain 1989, 32: 177-86.

Listeria, plasmids, antibiotic resistance,and food

SiR,—It was with interest that we read about clinical isolations inFrance of strains of Listeria monocytogenes with plasmid-mediatedresistance to multiple antibiotics (June 16, p 1422; Aug 11, p 375).L monocytogenes had previously been thought susceptible to

antibiotics active against gram-positive bacterial Dr MacGowanand colleagues (Aug 25, p 513) report that plasmid-mediatedmultiresistance in L monocytogenes has not been observed or is veryrare in the UK, and routine sensitivity tests on clinical isolates arenot usually indicated.We have for some time been interested in the incidence of

antibiotic-resistant and plasmid-bearing strains of Listeria sppisolated from the food environment. In a survey of raw milk fromOntario all listeria isolates were tested by disc assay for susceptibilityto nine commonly used antimicrobial agents. Only 2 of 26 strains ofL innocua were found resistant to any antibiotic (30 I1g tetracycline).None of 17 L monocytogenes isolates nor 1 L welshimeri isolate wasresistant to any antibiotic. Subsequently these and additionalisolates from raw milk were screened for plasmid DNA.4 OnlyL innocua strains harboured plamids (8 from 27 strains), but none of

19 L monocytogenes and 2 L welshimeri contained extrachromosomalDNA. The 2 strains of tetracycline-resistant L innocua did notcontain plasmids. Resistance in these instances appears to be

chromosomally mediated. We have extended antibiotic

susceptibility testing to include all 195 strains of listeria (110L monocytogenes, 63 L innocua, 12 L welshimeri, 5 L seeligeri, 3L ivanovii, 1 L grayi, and I L murrayz) in our collection of clinical,food, and environmental isolates from around the world. Apartfrom the two aforementioned L innocua strains (raw milk;non-plasmid-mediated tetracycline resistance, 30 Ilg) we havefound only 1 strain of L monocytogenes resistant to any antibiotic

(clinical source; potentially plasmid-mediated streptomycinresistance, 10 fig).Thus our findings are generally in agreement with previous

reports indicating susceptibility to antibiotics active against gram-positive bacteria. A small proportion of foodborne andenvironmental isolates may contain plasmids, which are

predominantly cryptic. None characterised to date has carrieddeterminants for resistance to any of the antibiotics tested. Thisevidence suggests that infection due to ingestion of foodbome,multiresistant strains of L monocytogenes is unlikely. Unless someunusual events are affecting propagation of antibiotic-resistantlisteria in the French food supply, a mechanism other than this mostlikely explains the isolation of plasmid-mediated multiresistantstrains from the two cases in France. Possibly some other

community-acquired or nosocomial route of infection may haveoccurred. More probably the strains of L monocytogenes acquiredresistance in vivo. The fact that this was reported to have occurredin the absence of selective pressure raises intriguing questionsregarding the mode of transmission and the mechanism of

acquisition of the R-factors. Fistrovici and Collins-Thompson4have suggested that listeria strains may acquire plasmids via thefaecal route where transfer of genetic information is more likely tohappen. Dr Quentin and colleagues (Aug 11) have intimated thatresistance factor transfer may occur in the human bowel and

vagina/cervix. Clearly these are enigmatic new developments in thecontinuing listeria saga.

Department of Environmental Biology,Ontario Agricultural College,University of Guelph,Guelph, Ontario, Canada N1G 2W1

PETER J. SLADEDAVID L. COLLINS-THOMPSON

1. Hawkins AE, Bortolussi R, Issekutz AC. In vitro and in vivo activity of variousantibiotics against Listeria monocytogenes type 4b. Clin Invest Med 1984; 7: 335-41.

2. Reynaud A, Espaze EP, Papin S, Courtieu A-L. Study of the sensitivity to antibioticsof 139 strains of Listeria monocytogenes serotyped by the French National ReferenceCentre in 1983. Ann Microbiol (Inst Pasteur) 1984; 135B: 331-39.

3. Slade PJ, Collins-Thompson DL, Fletcher F. Incidence of Listeria species in Ontarioraw milk. Can Inst Food Sci Technol J 1988; 21: 425-29.

4. Fistrovici E, Collins-Thompson DL. Use of plasmid profiles and restrictionendonuclease digest in environmental studies of Listeria spp from raw milk. Int JFood Microbiol 1990; 10: 43-50.

Combination diuretic therapy for severerefractory nephrotic syndrome

SIR,-Kiyingi et all reported the results of treatment of severecongestive heart failure with metolazone, a diuretic. Nephroticsyndrome is another disease for which diuretics can be expected tobe effective but we sometimes encounter patients with oedema whodo not respond to standard diuretics. For the treatment of suchpatients we have developed a combination diuretic therapy that isoften effective in refractory oedema associated with nephroticsyndrome. In nephrotic syndrome that has not yet progressed touraemia the combination is used to manage the oliguria in the hopeof a response before other treatments, including steroids, can beeffective. The three diuretics used are frusemide, ethacrynic acid,and chlorthalidone, and the usual daily doses are 120 mg, 75 mg, and150 mg, respectively.As shown in the table this combination reduced oedema

associated with nephrotic syndrome in patients whose oedema hadbeen refractory to frusemide alone or with either of the other twoagents. In cases 1-4 large doses of frusemide had been ineffective.

Urine volume began to increase on the first day and reached apeak a few days later, when urinary excretion of sodium also peaked.