CAMPYLOBACTER ENTERITIS DURING DOXYCYCLINE PROPHYLAXIS FOR MALARIA IN THAILAND

578 Clinical oncologists are continually reminded of the toxicity patients suffered. Carboplatin is a better tolerated platinum analogue than cisplatin and has equal efficacy. Its introduction

constitutes a further advance in clinical cancer care. The fact that financial considerations may prevent National Health Service clinicians from using it should not colour our interpretation of the clinical data. Division of Medicine, Institute of Cancer Research and Royal Marsen Hospital, Sutton, Surrey SM2 5NG

A. H. CALVERT

Department of Radiotherapy and Oncology, Royal Marsden Hospital

A. HORWICH

Department of Medical Oncology, Charing Cross Hospital, London

E. S. NEWLANDS R. BEGENT G. J. S. RUSTIN

Department of Medical Oncology, University of Glasgow

S. B. KAYE

Department of Medical Oncology, University of Newcastle on Tyne

A. L. HARRIS

CRC Wessex Regional Medical Oncology Unit, Southampton General Hospital,

C. J. WILLIAMS

Department of Medical Oncology, St Bartholomew’s Hospital, London

M. L. SLEVIN

1. Calvert AH, Harland SJ, Newell DR, et al. Early clinical studies with Cis-diammine-1, 1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 1982; 9:

140-47 2.

Wiltshaw E. Ovarian trials at the Royal Marsden. Cancer Treat

Rev

1985; 12 (suppl A).

67-71

3. Von Hoff DD. Whither carboplatin?—a replacement for or an alternative to cisplatin. J Clin Oncol 1987; 5: 169-71. 4. Consumers Association. Cancer chemotherapy. carboplatm versus cisplatin. Drug Ther Bull 1987; 25: 67-68. 5. Smith IE, Evans BD, Gore ME, et al. Carboplatin (paraplatin; JM8) and etoposide (VP-16) as first line combination therapy for small-cell lung cancer. J Clin Oncol 1987; 5: 185-89. 6. Forastiere AA, Natale RB, Takasugi BJ, Goren MP, Vogal WC, Kudla-Hatch V. A phase I-II trial of carboplatin and 5-fluorouracil combination chemotherpay in advanced carcinoma of the head and neck. J Clin Oncol 1987; 5: 190-96. 7. Daugaard G, Rossing N, Rorth M. Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose. Cancer Chemother Pharmacol 1988; 21: 163-67. 8. Ozols RF, Behrens BC, Ostchega Y, Young RC. High dose cisplatin and high dose carboplatin in refractory ovarian cancer. Cancer Treat Rev 1985; 12 (suppl A): 59-65. 9. Granowetter L, Rosenstock JG, Packer RJ. Enhanced cisplatin of neurotoxicity in pediatric patients with brain tumors J Neurooncol 1983; 1: 293-97. 10. McHaney VA, Thibadoux G, Hayes FA, Green AA. Hearing loss in children receiving cisplatin chemotherapy J Pediatr 1983; 102: 314-17. 11. Adams M, Rocker I, Kerby IJ, Johansen K, Franks CR. Randomised trial of cisplatin (CDDP) versus carboplatin (JM8) as first line therapy in advanced adenocarcinoma of the ovary. Proc fifth NCI/EORTC symposium on new drugs in cancer therapy. Oct 22-24, 1986, Amsterdam, The Netherlands, 1986: Abstr 1.13. 12. ten Bokkel Huinink WW, van der Burg MEL, van Oosterom AT, Dalesio O, Rotmensz JB. Carboplatin replacing cisplatin in combination chemotherapy for ovarian cancer. a large scale randomised phase III trial of the gynecological cancer cooperative group of EORTC. Proc Am Soc Clin Oncol 1986; 6: 118 (abstr).

CAMPYLOBACTER ENTERITIS DURING DOXYCYCLINE PROPHYLAXIS FOR MALARIA IN THAILAND

SIR,-Weekly prophylaxis against falciparum malaria is no longer effective in Thailand because of high-level resistance to chloroquine and ’Fansidar’ (pyrimethamine-sulfadoxine). Doxycycline 100 mg daily has been shown to prevent falciparum malaria among refugees along the Thai-Burmese border,’ and it is now being used for malaria prophylaxis for US soldiers coming to Thailand for field exercises. Doxycycline has also been used to prevent travellers’ diarrhoea.2 In Peace Corps volunteers doxycycline taken daily prevented travellers’ diarrhoea but in Thailand and Honduras where enterotoxigenic Escherichia coli (ETEC) are frequently resistant to tetracycline, doxycycline was only marginally effective.3.4 We have looked at the causes of diarrhoeal disease among US soldiers taking doxycycline prophylaxis in Thailand. From July 24 to Aug 28, 1987, 1155 US soldiers came to Thailand to take part in a field training exercise. 296 soldiers from

military units in the United States were stationed at a Thai military base near Lopburi in central Thailand and 857 soldiers from Hawaii were stationed at a base near Korat, 150 km north-east of Lopburi. Both groups of soldiers were instructed to take doxycycline 100 mg daily while in Thailand, starting 1 week before arrival and continuing for 6 weeks after leaving Thailand. Soldiers with acute gastrointestinal illnesses were seen at temporary field hospitals by medical auxiliaries who used a standardised questionnaire to obtain information about the acute illness. Stool specimens or rectal swabs from ill patients were transported in Cary-Blair transport media to Bangkok where they were processed for enteric pathogens.s Campylobacters were isolated by the membrane filtration method on non-selective media at 37°C.6 The minimum inhibitory concentration (MIC) for campylobacter was estimated for tetracycline, erythromycin, and ciprofloxacin.6 Campylobacter strains were serotyped by the Lior method? For salmonella and ETEC, antimicrobial resistance was determined by the Bauer-Kirby disk sensitivity method.8 For statistical analysis we used a two-tailed Fisher’s exact test. Campylobacterjejuni was isolated from 14 (50%) of 28 soldiers with acute gastrointestinal illnesses from whom stool specimens were received. 3 soldiers were co-infected with Salmonella spp, I with ETEC, and 1 with Plesiomonas. Cjejuni was isolated from 8 soldiers training in Korat. They were Lior serotype 11 (3 cases), 19 (3 cases), 36 (1 case), and 1 untypable. Cjejuni was isolated from 6 soldiers in Lopburi. They were Lior serotypes 4 (2 cases), 28 (2 cases), 1 (1 case), and 1 untypable. All campylobacter isolates were resistant to tetracycline. The MIC 5. of tetracycline for 50% of isolates was 64 g/ml (range 32 to over 128). All isolates were susceptible to erythromycin (MIC,,, 2 g/ml [range 1-4]) and to ciprofloxacin (MICso 0-12 )ig/ml [range 0’06-0’24 The salmonella isolates were resistant to tetracycline and co-trimoxazole. The ETEC strain was sensitive to all antibiotics, including

tetracycline. The illness associated with campylobacter infections was characterised by abdominal pain (82 %), diarrhoea (73 %), and fever (64%). Bloody diarrhoea was observed in 2 soldiers. Soldiers infected with C jejuni more often had an oral temperature above 38’3°C and were more likely to have been treated with antibiotics for their illness than soldiers who presented with diarrhoea and had a negative culture for enteric pathogens (p = 0-008 and p = 0014,

respectively). Without a control group we do not know if doxycycline prevented travellers’ diarrhoea. 28 cases of diarrhoea among 1153 soldiers is not a high attack rate. However, in a post-deployment questionnaire 129 (17%) of 770 soldiers stationed in Korat reported an episode of diarrhoeal disease while in Thailand. The isolation of C jejuni from 50% of the soldiers with diarrhoea while taking doxycycline is notable. Since many of the studies evaluating the efficacy of doxycycline were done before modem campylobacter isolation methods were used, the role of C jejzini as a cause of travellers’ diarrhoea may have been underestimated. Campylobacter spp were isolated from 18% of 586 Thai children under 5 years old with diarrhoea,9 making it one of the most commonly isolated enteropathogens in Thailand. In more recent studies among tourists and foreign residents with diarrhoea, Campylobacter spp were also isolated from 15% of 269 persons in BangladeshlO and 14% of 191 persons in Nepal." Tetracycline and erythromycin resistant Campylobacter spp are common in Bangkok. In a previous study 65% of C jejuni isolates and 80% of C coli isolates were resistant to tetracycline, and 11 % of Cjejuni and 46% of C coli were resistant to erythromycin.6 The 14 Cjejuni isolates belonged to six different Lior serotypes, suggesting that they were from multiple sources.

While campylobacter infections among Thai children are usuall! mild or symptom-free,9 we observed that campylobacter can cause a severe enteritis associated with bloody diarrhoea and abdominal pain in non-immune hosts. This supports observations m Bangladesh that foreigners have a dysentry-type illness when infected with campylobacter acquired in the developing world. much the same as when infected with campylobacter in developed countries." The similarity of both serotypes and clinical illness suggests that there are not major differences in campylobacte:

579 strains in developing and developed countries; however, the degree of antimicrobial resistance is increased, at least in Thailand. Campylobacter spp are also resistant to co-trimoxazole, which is also commonly recommended for treatment of travellers’ diarrhoea. Since all isolates in this study were susceptible to ciprofloxacin, the new quinoline drugs would be useful for treating severe infections."" Little is known about the untoward effects of doxycycline for malaria prophylaxis. This study suggests that campylobacter enteritis should be considered in travellers with diarrhoea who have been taking doxycycline. Department of Bacteriology,

DAVID N. TAYLOR CHITTIMA PITARANGSI PETER ECHEVERRIA

Armed Forces Research Institute of Medical Science, Bangkok 10400, Thailand Division of Preventive

Medicine, Army Institute of Research, Washington, DC, USA Walter Reed

BENEDICT M. DINIEGA

Pang LW, Limsomwong N, Boudreau EF, Singharaj P. Doxycycline prophylaxis for falciparum malaria. Lancet 1987; i: 1161-64. 2 Sack RB. Antimicrobial prophylaxis of travelers’ diarrhoea: a selected summary. Rev Infect Dis 1986; 8 (suppl 2): S160-66. 3. Echeverria P, Sack RB, Blacklow NR, Bodhidatta P, Rowe B, McFarland A. Prophylactic doxycycline for travelers’ diarrhea in Thailand further supportive evidence of Aeromonas hydrophila as an enteric pathogen. Am J Epidemiol 1984; 1

120: 912-21. 4. Sack RB, Santosham M, Froehlich JL, Medina C, Orskov F, Orskov I Doxycycline prophylaxis of travelers’ diarrhea in Honduras, an area where resistance to

5

6

doxycycline is common among enterotoxigenic Escherichia coli. Am J Trop Med Hyg 1984; 33: 460-66. Taylor DN, Echeverria P, Pal T, et al. The role of Shigella species, enteroinvasive Escherichia coli, and other enteropathogens as causes of childhood dysentery in Thailand J Infect Dis 1986; 153: 1132-38 Taylor DN, Blaser MJ, Echeverria P, Pitarangsi C, Bodhidatta L, Wang WLL. Erythromycin-resistant campylobacter infections in Thailand Antimicrob Ag

Chemother 1987; 31: 438-42. 7 Lior H, Woodward DL, Edgar JA, LaRoche LJ, Gill P. jejuni by slide agglutination based

on

Serotyping of Campylobacter heat-labile antigenic factors. J Clin Microbiol

1982; 15: 761-68. 8 Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol 1966; 45: 493-96. 9 Taylor DN, Echeverria P, Pitarangsi C, Seriwatana P, Bodhidatta L, Blaser MJ. Influence of strain characteristics and immunity on the epidemiology of Campylobacter infections in Thailand. J Clin Microbiol 1988; 26: 863-68. 10 Speelman P, Struelens MJ, Sanyal SC, Glass RI. Detection of Campylobacter jejuni and other potential pathogens in travellers’ diarrhoea in Bangladesh. Scand J Gastroenterol 1983; 18 (suppl 84). 19-23. 11 Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BLP, Echeverria P. Etiology of diarrheal disease among travelers and foreign residents in Nepal.

JAMA (in press). CD, Johnson PC, DuPont HL, Morgan DR, Bitsura JA, de la Cabada FJ. Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers’ diarrhea: a placebo-controlled, randomized trial. Ann Intern Med 1987; 106:

12 Ericsson

216-20

HET, Diridl G, Stickler K, Wolf D. Clinical efficacy of ciprofloxacin compared with placebo in bacterial diarrhea. Am J Med 1987; 82 (suppl 4a):

13 Pichler

329-32

PLATELET SEROTONIN CONCENTRATION IN PATIENTS WITH FINGER-CLUBBING

SIR,-Dickinson and MartinI hypothesised that finger-clubbing in patients with respiratory disease may be initiated by plateletderived growth factor (PDGF). It was suggested that PDGF may be released in the digital arteries either from megakaryocytes or from platelet aggregates, which are not removed by the lungs in these patients, thus resulting in characteristic abnormal localised vascular proliferation.2 This suggests that the megakaryocytes/ platelet aggregates are undergoing activation and release of stored constituents. We have evidence that may indicate increased in-vivo platelet activation in patients with respiratory disease and finger-

clubbing. Blood

collected from 18 patients (aged 25-85) attending the respiratory unit, Northern General Hospital, Edinburgh. The diagnoses were: chronic obstructive airways disease (n = 7, including, in addition, 1 each of cor pulmonale and left ventricular failure); asthma/bronchiectasis (3); bronchial carcinoma (3); and 1 each of chronic asthma, Guillain-Barre syndrome/respiratory failure, aortic valve disease, ascites/pleural effusion, and cystic fibrosis/bronchiectasis. 8 patients (4 male, 4 female) had fingerclubbing, 10’ did not (6 male, 4 female). Platelet-rich plasma was prepared and serotonin was measured by radioimmunoassay.’ The was

Platelet serotonin concentration (mean, SE) in patients with respiratory disease with and without detectable finger-clubbing.

platelet serotonin concentration in the patients with fingerclubbing was significantly lower than in controls (figure; p < 0-05).

mean

Platelet serotonin concentration may be

a

useful indicator of

platelet activation in vivo,4 and so the difference we found in platelet serotonin concentration may reflect increased platelet activation in the patients with finger-clubbing. Since platelet alpha-granules are thought to release their constituents (eg, PDGF, p-thromboglobulin) at lower thresholds of stimuli than the dense granules,s which are the storage sites for serotonin, our results also suggest that the contents of the alpha-granules may be depleted in these patients. Whether platelet activation exists before the occurrence of finger-clubbing remains to be established. Department of Medicine, Western General Hospital, Edinburgh, EH4 2XU; Department of Medicine, Royal Infirmary, Edinburgh; and Respiratory Unit, Northern General Hospital, Edinburgh

IAIN F. GOW DAVID B. JONES JOHN BILLETT ANTHONY J. FRANCE CHRISTOPHER R. W. EDWARDS

CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987; ii: 1434-35. 2. Lovell RRM. Observations on the structure of clubbed fingers. Clin Sci 1950; 9: 1. Dickinson

299-321. 3. Gow IF, Corrie JET, Williams BC, Edwards CRW. The development and validation of an improved radioimmunoassay for serotonin in platelet-rich plasma. Clin Chim

Acta 1987; 162: 175-88. A, Frampton G, Cameron JS. Measurement of platelet release substances in glomerulonephritis. a comparison of beta-thromboglobulin (&bgr;-TG), platelet factor 4 (PF4), and serotonin assays. Thromb Res 1980; 19: 177-89. 5. Witte LD, Kaplan KL, Nossel HL, Lages BA, Weiss HJ, Goodman DS. Studies of the release from human platelets of the growth factor for human arterial smooth muscle cells. Circ Res 1978; 42: 402-09 4. Parbtani

ANTI-LFA1 MONOCLONAL ANTIBODY AND BONE MARROW GRAFT REJECTION IN ADULTS SIR,--Graft rejection is a major impediment to the successful use of T cell

depletion in the prevention of graft-versus-host disease (GVHD).1 Fischer and colleagues3 showed that rejection could be abolished by in-vivo administration of an anti-LFA1 (CD 18) monoclonal antibody to the recipients of T cell depleted HLA mismatched bone marrow transplants (BMT). These results prompted us to use this monoclonal antibody, with the same regimen, in association with cyclophosphamide and total body irradiation (12 Gy) before T cell depleted BMT" in 9 adults with leukaemia, who received marrows from HLA-identical siblings. Unfortunately, of the 9 patients, 2 failed to engraft, and 2 had delayed rejections. This clear difference from encouraging results in