Ciprofloxacin for treating cholera

THE LANCET

pressure and the dependent variable (eg E/A ratio or IVRT). Alternative approaches are possible, as suggested by Kristensen and Høegholm, but all are equally arbitrary. The methodology for the stiffness index is described in detail in the reference cited where it was studied in both muscular (eg, brachial) and elastic (eg, carotid, femoral, and abdominal aorta) arteries and, although wide variations were found in the brachial artery in response to changes in sympathetic tone, the stiffness index remained relatively constant in the carotid artery. In our article we conceded that “no single expression can adequately describe the mechanical behaviour of an artery throughout the cardiac cycle”, and for this reason we listed other indices, including the absolute distensibility, Peterson’s elastic modulus, and the distensibility coefficient. The message of our article is that there is a need for a standardised and widely accepted definition of white-coat hypertension, and we repeat our principal conclusion that outcome studies are required to resolve whether or not patients with white-coat hypertension require long-term treatment.

patients taking tacrolimus, and are analogous to previous observations that black renal transplant recipients have a lower bioavailability with regard to cyclosporin.2,3 The mechanisms underlying this observation are unclear, but do not appear to relate to differences in compliance or physique. It is possible that racial variation in cytochrome P450 3A4 may play a part, as this is responsible for tacrolimus metabolism, and other cytochromes are known to be differentially distributed in blacks.4,5 There are several important implications. First, mean dosage requirements of nearly twice “normal” in the black population may have considerable impact upon the cost of medication: mean £3860 versus £1970 for tacrolimus at this institution for the first 3 months alone. Second, the data caution against the administration of low-dose tacrolimus to black transplant recipients in the early postoperative period; recommended dosage regimens may require amendment. Third, it is possible that the increased dose of tacrolimus required in blacks may have an adverse influence upon safety or side-effect profiles. Formal pharmacokinetic studies are in progress to address these issues further.

*Stephen Glen, Henry Elliott, Kennedy Lees, John Reid Department of Cardiology, Western Infirmary, Glasgow G11 6NT, UK

*Peter A Andrews, Manoj Sen, René W S Chang Renal Unit, St George’s Hospital, London SW17 0QT, UK

Racial variation in dosage requirements of tacrolimus SIR—Tacrolimus (FK506) is increasingly used as first-line and rescue immunosuppression in renal transplantation. The oral dosage for induction therapy is typically 0·1 mg/kg twice daily when used in conjunction with low-dose steroids, aiming for trough concentrations of 10–15 ng/mL. We report a racial variation in dosage requirements that may affect starting dosage, costs, and side-effect profiles. 27 patients have received tacrolimus at our institution for a minimum of 3 months after transplantation. Seven patients were black, while the remainder were of white (n=16) or Asian (n=4) descent. Tacrolimus dosages were adjusted on the basis of trough concentrations taken 12–16 h after the evening dose, and were measured with a semi-automated microparticle enzyme immunoassay.1 The mean doses of tacrolimus required to achieve standard trough concentrations in these groups are shown in the table. The mean dose in the black group was 96% higher than in the white/Asian group, and remained higher at all times after transplantation (p<0·001). Of note, six of seven black patients required doses in excess of 20 mg daily (0·28 mg/kg) in the first month, compared with two of twenty in the control group (p<0·001). Mean tacrolimus dosage or concentrations were not related to differences in sex, age, transplant function, incidence of diabetes or hepatitis, or body mass index. Similarly, there was no difference between the groups in patient compliance, as measured by frequency of repeat prescription, or adjunctive therapy known to affect tacrolimus metabolism. Surprisingly, given the recommendation to prescribe on a mg/kg basis, there was no correlation between body weight and dosage requirements (r =0·001). Our data suggest that important differences in absorption and/or metabolism may exist between black and non-black

Month 1 Month 2 Month 3 Mean months 1–3

Black recipients (n=7)

Non-black recipients (n=20)

24·8 (1·8) 26·1 (2·65) 21·2 (3·1) 24·0 (1·2)

14·5 (0·9) 11·9 (1·2) 10·4 (1·0) 12·7 (0·7)

Table: Mean (SE) dose requirements of tacrolimus (mg per day) by race after renal transplantation

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Grenier FC, Luczkiw J, Bergmann M, et al. A whole blood FK506 assay for the IMx analyzer. Transplant Proc 1991; 23: 2748–49. Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54: 205–18. Schroeder TJ, Hariharan S, First MR. Variations in bioavailability of cyclosporine and relationship to clinical outcome in renal transplant subpopulations. Transplant Proc 1995; 27: 837–39. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current status of knowledge of cytochromes P450(CYP) 2D6 and 2C19. Clin Pharmacokinet 1995; 29: 192–209. Gut A, Chaloner C, Schofield D, et al. Evidence of toxic metabolic stress in black South Africans with chronic pancreatitis. Clin Chim Acta 1995; 236: 145–53.

Ciprofloxacin for treating cholera SIR—Khan and colleagues (Aug 3, p 296)1 report a large study of ciprofloxacin therapy for cholera in Bangladesh and we wish to confirm the efficacy of this treatment in multidrug-resistant V cholerae infections. Between Oct 18 and Dec 4, 1994, there was an outbreak of cholera in 12 inhabitants of the Puglia region, southern Italy (a vast epidemic has troubled nearby Albania since 1994). Ten of 12 cases were diagnosed in our department2 including seven men (mean age 61·6 years, range 43–88). The median incubation period was 48 h (range 24–96). All patients had watery diarrhoea with a median of 15 stools daily (range three to 50). Six patients also presented with vomiting (one to two episodes). One patient had been previously treated with oral amoxicillin (2 g per day for 6 days) and another with oral cotrimoxazole (2·88 g per day for 5 days) and subsequently with intravenous ampicillin (3 g per day for 2 days). In both these cases, treatments did not provide clinical improvement or bacterial eradication. At hospital admissions, two patients were mildly dehydrated and another had severe dehydration with acute renal failure. Faecal samples for identification of V cholerae were collected on admission and daily thereafter until negative results were obtained for three consecutive cultures. Vibrio colonies were tested for antibiotic susceptibility according to the KirbyBauer method.3 Serotyping and biotyping were performed in the Bacteriology Laboratory of the Istituto Superiore di Sanità (Rome). Faecal samples collected at admission were positive for V cholerae (serotype Ogawa, biotype El Tor) in all

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patients. One patient was co-infected with Salmonella typhi. The tests showed that all strains were resistant to cotrimoxazole, tetracycline, doxycycline, streptomycin, and chloramphenicol, and that they were susceptible to ciprofloxacin, gentamicin, tobramicin, ampicillin, nalidixic acid, and cefalotin. This pattern of multidrug-resistance was also a characteristic of strains isolated during the Albanian epidemic.4 Nine of our department’s ten patients were eligible for the evaluation of treatment efficacy. These nine were given oral ciprofloxacin (500 mg twice daily for 10 days). Treatment was initiated a median 5·5 (range 2–10) days from the onset of symptoms. In all those treated with ciprofloxacin there was complete disappearance of the symptoms within a median of 36 (range 12–96) h. Faecal cultures became negative within a median of 24 (range 12–48) h from start of the therapy. Although limited, our experience shows the growing importance of multidrug-resistant V cholerae infections—not only in developing countries, but also in industrialised states bordering on epidemic or endemic areas. At least in multidrug-resistant cases, treatment with ciprofloxacin could represent a safe and effective alternative to tetracyclines. There is some apprehension about emergence of resistant strains. We postulate that a single-dose regimen, even though clinically effective, might not always guarantee complete clearance of V cholerae, despite negative results from present methods of detection. Therefore, selection and spread of ciprofloxacin-resistant strains might be favoured. We believe that a short course of the drug, rather than a single dose, should be preferred for cholera treatment, at least until microbiological efficacy of single-dose therapy is confirmed. *Paolo Maggi, Sergio Carbonara, Teresa Santantonio, Giuseppe Pastore, Gioacchino Angarano *Institute of Infectious Diseases, University of Bari, 70124 Bari, Italy; and Department of Infectious Disease, Hospital Fallacara, Triggiano

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Khan WA, Bennish ML, Seas C, et al. Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae O1 or O139. Lancet 1996; 348: 296–300. Maggi P, Carbonara S, Fico C, et al. Epidemiological, clinical and therapeutic evaluation of the Italian cholera epidemic in 1994. Euro J Epid (in press). Manual for laboratory investigations of acute enteric infections. Geneva: World Health Organization, 1987. Cholera in Europe. Wkly Epidem Rec WHO 1994; 43: 322–23.

There is now an International Standards Organisation (ISO) standard shoulder colour of green for NO cylinders, and British Oxygen Company Special Gases have standardised the cylinder body colour to gold. A pin index system has also been developed for nitric oxide according to ISO 407 and a product specific outlet point has also been developed for piped NO according to Health Technical Memorandum 2022. Warren and Higenbottam describe administration systems for NO as complex and state a need for a safe administration system. We disagree that the system is complex, but any perceived complexity is necessary to guarantee the safe administration of NO, something we are sure that your commentators will applaud. We do not understand the reference to ambulatory administration of NO since there are no current applications for inhaled NO in the ambulatory patient. Finally, they state that there was need to define the lowest clinical effective dose for inhaled NO. This work has been done and Gerlach et al4 recommended that NO be titrated to achieve the minimum effective dose for each patient. The lack of clinical efficacy of inhaled NO at improving oxygenation in chronic obstructive airways disease (COAD) does not demonstrate uncertainty about the effects of inhaled NO on gas exchange but rather that the ventilation/perfusion abnormality of COAD differs from that of ARDS. The gas exchange abnormality of COAD was always unlikely to respond to inhaled NO. Interestingly, the article cited did demonstrate a predictable effect of inhaled NO in COAD—that of reduced mean pulmonary artery pressure.5 We agree that caution must be shown with any new form of treatment. It should be realised that, in contrast to many widely used forms of therapy, researchers and clinicians developing this new and promising form of therapy are indeed trying to produce quality evidence for the efficacy of inhaled NO and are attempting to ensure the safety of both patients and staff. *B H Cuthbertson, S Stott, N R Webster Intensive Therapy Unit, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZD, UK

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Inhaled nitric oxide SIR—Warren and Higenbottam’s commentary (Sept 7, p 629)1 is unhelpful. Inhaled nitric oxide (NO), like many other forms of therapy used in intensive therapy units (ITU), is indeed an unlicensed form of treatment, and it is correct to warn doctors that they are individually responsible for its use. Two large multicentre randomised controlled trials are underway in Europe and America on the use of NO in acute respiratory distress syndrome (ARDS), and will provide the answers we all seek. Hopefully, this will be followed by the issue of a licence for this indication. 85% of treatments used in ITU have no evidence to support their use.2 Work underway to prove efficacy of NO should be commended. The danger of explosion with cylinders of NO is overstated since there is no greater risk than for oxygen cylinders. Warren and Higenbottam cite complications such as pulmonary oedema and methaemoglobinaemia, although these effects do not occur within the clinical dose range or indeed at far higher doses.3 The use of calibrated flowmeters and inspiratory monitoring reduce the possibility of potentially dangerous overdose.

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Warren JB, Higenbottam T. Caution with use of inhaled nitric oxide. Lancet 1996; 348: 629–30. Shoemaker WC. Critical care research in the 1990s: how our perceptions effect creativity. Crit Care Med 1994; 22: 1040–43. Young JD, Dyar O, Xiong L, Howell S. Methaemoglobin production in normal adults inhaling low concentrations of nitric oxide. Intens Care Med 1994; 20: 581–84. Gerlach H, Rossaint R, Pappert D, Falke KJ. Time-course and doseresponse of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome [see comments]. Eur J Clin Invest 1993; 23: 499–502. Barbera JA, Roger N, Roca J, et al. Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease. Lancet 1996; 347: 436–40.

SIR—We agree with Warren and Higenbottam1 that a safe administration system is required for the inhalational delivery of nitric oxide (NO) therapy. This need also extends to ensuring appropriate scavenging of the exhaust gases, as the following report illustrates. A 28-year-old paediatric nurse contacted the occupational health department a few days after feeling ill at work. For 8 h of a 12 h shift she had been attending a neonate in an incubator. NO was being given via nasal cannulae at a concentration of 7·5 parts per million (ppm) with oxygen at 24–30%. Inspired gas was monitored with an NO fuel cell electrode. Nitrogen dioxide (NO2) was not monitored. The side doors of the incubator were open, adjacent to her sitting position. Ultraviolet (UV) light was not in use, neither was anaesthetic gas. The nurse was not on any medication and had been in good health. She had a history of migraine, but

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