1508
presented shows that the results obtained from airborne sampling are far from repeatable: fig 1 shows a similar ranking of repeat samples, but all are about 60% lower. A glaring omission is that mattress dust, the richest source of mite allergen, was not sampled. Despite the limitations of measuring floor dust Price et al
evidence
found a correlation between this measure and sensitisation. The level of 2 ug Der p 1/g proposed2 for sensitisation to mites is a working value for which there is increasing epidemiological data. The lower level of 05 )g/g that Price et al found may reflect this threshold when mattress dust is not assayed. There are also two areas of misinterpretation of previous work.3 .3 Price et al claim that particles 10 Etm or more in diameter cannot penetrate an infant’s airway. Increasing particle size simply reduces the percentage that enters the lung,4,5 and we know of no evidence that particles of this size are never inhaled. Price et al also say sampling rates of 20 1/min clear allergen from domestic air. This sampling rate is similar to the minute volume of an adult. The total volume of air sampled in our 1981 study3 was 400 litres, very similar to the total volume sampled in Price’s paper, and less than 10% of the volume of the rooms studied. Reservoir measurements have proved to be both a valid index of exposure6,7 and robust. Sampling methods, including airborne allergen measurements, were considered by two international workshops/,8 and reservoir measurements were endorsed as being relevant and the most practicable. A prospective study of allergen exposure based on reservoir measurements has been completed in the UK and there was a significant relation between exposure in infancy and childhood asthma.9 If airborne sampling is undertaken in future epidemiological studies, floor and mattress dust samples should also be obtained. Division of Allergy and Clinical Immunology, University of Virginia, Charlottesville, Virginia 22908, USA
RICHARD SPORIK MARTIN CHAPMAN THOMAS PLATTS-MILLS
Chapman MD, Heymann PW, Luczynska CM. Measurements of airborne allergen using immunoassays. Immunol Allergy Clin N Am 1989, 9: 269-83. 2. Anon Report of an international workshop Dust mite allergens and asthma. a worldwide problem J Allergy Clin Immunol 1989; 83: 416-27. 3. Tovey ER, Chapman MD, Wells CW, Platts-Mills TAE. The distribution of dust mite allergen m the houses of patients with asthma Am Rev Respir Dis 1981; 124: 630-35 4. Svartengren M, Falk R, Linnman L, et al Deposition of large particles in human lung Exp Lung Res 1987, 12: 75-88. 5. Harper GJ, Morton JD. The respiratory retention of bacterial aerosols: experiments with radioactive sports. J Hyg 1953, 51: 372-85. 6. Lau S, Falkenhorst G, Weber A, et al. High mite-allergen exposure increases the nsk of sensitisation m atopic children and young adults. J Allergy Clin Immunol 1989; 84: 718-25 7 Charpin D, Birnbaum J, Haddie E, Genard G, Toumi M, Vervolet D. Attitude and allergy to house dust mites: an epidemiological study in primary school children. J Allergy Clin Immunol 1990, 85: 185 (abstr) 8 Second International Workshop on Dust Mite Allergens and Asthma (Minster Lovell, 1. Platts-Mills TAE,
9.
Oxon, September, 1990). Sporik R, Holgate ST, Platts-Mills RAE, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood—a prospective study. N Engl J Med 1990, 323: 502-07.
SIR,-Dr Price and colleagues found no correlation between floor dust levels and airborne levels of mite allergens.’ This led to the conclusion that air sampling should be used to assess inhaled allergen exposure. As Price et al pointed out, asthma is triggered by the airborne allergens in the domestic environment which contain, besides mite allergens, airborne moulds that have been implicated in allergic asthma.2 We have measured airborne mould levels in the homes of asthmatic patients3 and found results consistent with Price and colleagues’ study. There was no correlation between dust mould and airborne mould concentrations, and neither wall humidity nor indoor temperature had any effect on dust or airborne moulds. Price et al conclude that furnishings, ventilation, and other factors affecting airborne allergen levels must be taken into account in the assessment of exposure. In our study, although airborne mould concentrations did not depend on the floor types, indoor mould concentrations were influenced by the type of housing. Levels of airborne moulds were higher in recent houses than in old ones, and in collective housing than in individual homes (especially
in winter, a poor season for moulds). Poor ventilation and insulation material may be important factors that increase the level of moulds exposure. In view of Price and colleagues’ hypothesis, this could also be true for airborne mite allergens. J. M. TUNON DE LARA Department of Respiratory Disease, R. MARTHAN Hôpital Haut-Lévêque, A. TAYTARD CHU Bordeaux, F-33604 Pessac, France 1 2
Price JA, Pollock I, Little SA, Longbottom JL, Warner JO. Measurements of airborne mite allergen in homes of asthmatic children Lancet 1990; 336: 895-97. Salvaggio J, Aukrust L. Mould induced asthma J Allergy Clin Immunol 1981; 68:
327-46. 3. Tunon de Lara JM, Tessier JF, Lafond Grellety J, patients homes Aerobiologia 1990, 6: 98-101.
et
al. Indoor moulds in asthmatic
SiR,-What is in the carpet is certainly not as important as what is in the air. In 1976 we demonstrated in sensitive individuals a significant correlation between the concentration of particles in the inhaled air and a decrease in peak flow, but only for particle sizes below 2 pm.1 The reduction in peak flow was significantly greater only at times when the house was being swept or a vacuum cleaner was being used. The inference is that the carpet may be safe, whatever its content or composition, provided it is not being cleaned. Housedust-sensitive asthmatic children should stay away whilst the house is being cleaned, and for at least an hour afterwards. T. D. PRESTON L. SINCLAIR
Westminster Hospital. London SW1 P 2AP, UK
1. Clark RP, Preston TD, Gordon-Nesbitt DC, Malka
S, Sinclair L. The size of airborne dust particles precipitating bronchospasm in house dust sensitive children J Hyg (Camb) 1976; 77: 321-25.
Cyclophosphamide for chronic relapsing thrombotic thrombocytopenic purpura SIR,- If undiagnosed and untreated thrombotic thrombocytopenic (TTP) runs a fulminant course. Early appropriate plasma therapy and plasmapheresis reduces death rates in acute TTP, but purpura
for chronic relapsing TTP can pose difficulties. Dr Bird and her colleagues (Sept 1, p 565) report a 26-year-old woman whose chronic TTP responded well to cyclophosphamide (with other therapeutic measures). We describe a patient in whom cyclophosphamide proved beneficial in a somewhat similar clinical treatment
setting. A 53-year-old
presented in 1987 with progressive megakaryocytic thrombocytopenia (platelets less than 109/1), indirect hyperbilirubinaemia, uraemia, and non-immune haemolytic anaemia with fragmented red blood cells. Plasma values for von Willebrand factor antigen, P-thromboglobulin, and thromboxane-B2 were high, whereas prostacyclin metabolite (6-keto-prostaglandin-F) proved to be undetectable in plasma and in clotted whole blood. The presence of cytotoxic endothelial antibodies was also verified. She was immediately given fresh-frozen plasma with striking improvement, soon followed by serious relapse. Plasmapheresis was effective during the first relapse but not in the second, and splenectomy was therefore undertaken. The appearance of Howell-Jolly bodies post splenectomy indicated active splenic-tissue remnants. After splenectomy the relapsing pattern of the disorder did not change much, but thrombocytopenia, haemolysis, and renal insufficiency were less severe. Aspirin did not ameliorate her symptoms. In 1988 malignant lymphoma of T-cell origin was suspected (13-16 x 109/1 lymphocytes, 50-70% lymphocellular bone-marrow infiltration, Combined chemotherapy presence of T-cell markers). (cyclophosphamide, corticosteroid, and vincristine) resulted in long-term improvement of TTP-related symptoms, but vinca alkaloids were stopped later because of neurotoxicity. Since then she has received cyclophosphamide (brief infusion of 600-800 mg, sometimes repeated after a week) which was effective in achieving remissions on five occasions, remission usually lasting for 4-6
confusion,
months.
coma,
woman
severe
1509
Our patient provides further evidence that cyclophosphamide be regarded as a valuable therapeutic option in chronic relapsing TTP. Our patient probably also had an associated disease (T-cell lymphoma). Nonetheless cyclophosphamide infusions might be of therapeutic value in acute episodes of chronic relapsing TTP and in lengthening of otherwise short remission periods. can
Department of Medicine, University Medical School,
2nd
H-4012 Debrecen,
MIKLOS UDVARDY KALMAN RAK
Hungary
Ciprofloxacin
and
pseudomembranous
colitis SIR,-Dr Cain and Dr O’Connor (Oct 13, p 946) raise the spectre of ciprofloxacin being implicated in pseudomembranous colitis (PMC), and they advise caution in the use of this agent in acute diarrhoea. Ciprofloxacin’s activity against most anaerobes is very limited-indeed, the 90% inhibitory concentration (MIC) for ciprofloxacin against Clostridium difficile is 32 mg/1.1 Even though the faecal levels achieved exceed 32 mg/1 the loss of bactericidal activity under anaerobic conditions2 leads to the virtual lack of effect on the anaerobic faecal flora.3 Pecquet et aP observed no overgrowth or adverse effects with C difficile during their study. When the normal anaerobic intestinal flora is much reduced the protective factor against C difficile overgrowth is removed.’ During ciprofloxacin therapy only the Enterobacteriaceae are greatly reduced, changes in other genera being negligible. Antimicrobial agents most frequently associated with PMC are those with strong activity against anaerobes (eg, penicillins, cephalosporins, and clindamycin). Metronidazole and vancomycin have been implicated in relapses,s,6 even though they have been used successfully to treat C difficile infection. From spontaneous reports and from clinical trial data 14 cases of PMC involving ciprofloxacin have been recorded. However, over 40 million patients worldwide have been treated with this drug over the past 5 years, and in half the PMC cases the patient was taking or had recently received other antimicrobial agents. Causality is thus difficult to prove. To recommend, in cases of acute non-bloody diarrhoea, screening for ciprofloxacin-resistant C difficile would impose on microbiology laboratories a huge workload that might be irrelevant in view of the tenuous evidence for a role of ciprofloxacin in PMC. Research and
Development Department, Bayer UK, Newbury RG13 1JA, UK 1.
B. J. O’KEEFFE G. S. TILLOTSON
Barry AL. In-vitro activity of the fluoroquinolone compounds. Antimicrob News 1988;
5: 69-76. 2. Smith JT, Lewin CS. Chemistry and mechanisms of action of the quinolone antibacterials. In: Andriole VT, ed. The quinolones. London: Academic Press, 1988: 23-82. 3. Pecquet S, Ravoire S, Andremont A. Faecal excretion of ciprofloxacin after a single oral dose and its effect on faecal bacteria in healthy volunteers. J Antimicrob
Chemother 1990, 26: 125-29. Fekty R, Kim K-H, Batts DH, et al Studies on the epidemiology of antibiotic associated Clostridium difficile colitis. Am J Clin Nutr 1980; 33: 2527-32. 5. George WL, Volpicelli NA, Stiner DB, et al Relapse of pseudomembranous colitis after vancomycin therapy. N Engl J Med 1975; 30: 414-15. 6. George WL, Rolfe RD, Fmegold SM. Clostridium difficile and its cytotoxin in faeces of
4.
patients with antimicrobial agent associated diarrhoea and miscellaneous conditions. J Clin Microbiol 1982; 15: 1049-53.
SIR,-Dr Cain and Dr O’Connor mention that quinolones have not implicated in pseudomembranous colitis. Although this is true of ciprofloxacin, ofloxacin has been associated with pseudomembranous colitis in one case reported in Englishlanguage publications.We have recently seen a 72-year-old patient treated with maintenance peritoneal dialysis because of analgesic nephropathy. She received a 2-week course of ofloxacin, three months before the onset of colitis, for a coliform bladder infection. Bladder polyps were found, and before a planned cystoscopic resection had a right been
cerebral infarct. She was treated with phenoxymethylpenicillin orally for 1 week for a suspected aspiration pneumonia (within 1 week of stopping ofloxacin). 10 weeks before the onset of colitis she
received one dose of intravenous (iv) vancomycin 1 g together with iv netilmicin 200 mg, after an arteriovenous shunt. A second course of ofloxacin was given for cough with green sputum and fever. 2 days later she had abdominal pain, diarrhoea, and toxic clonic dilatation, and stool specimens were positive for Clostridium difficile and toxin. She was treated with vancomycin and metronidazole, but had a prolonged ileus and died 2 weeks later with a left cerebral infarct. What worries us especially about this case is the rapid onset of colitis shortly after starting the second course of ofloxacin. Pseudomembranous colitis is recognised in uraemia, but the suppressive role of antibiotics on native resistance to C difficile colonisation is presumed to be of pathogenic importance 2 The rapid effect of ofloxacin on the gut flora of a patient being treated with antibiotics could have led to an especially speedy onset of colitis. In view of the low in-vitro sensitivity of C difficile to several quinolonesthese drugs should not be used in pseudomembranous colitis. Repeated use in patients with diarrhoea should also be avoided if possible. S. L. CHEW Department of Nephrological Hypertension, R. DAELEMANS A Z Stuivenberg, B 2060 Antwerp, Belgium R. L. LINS 1. Dan M, Samra Z. Clostridium difficile colitis associated with ofloxacin therapy.
Am J
Med 1989; 87: 479. 2 Larson HE. Botulism, gas gangrene and clostridial gastrointestinal infections. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine. Oxford: OUP, 1987: 5.270-77. 3. Chow AW, Cheng N, Bartlett KH. In vitro susceptibility of Clostridium difficile to new beta-lactam and quinolone antibodies. Antimicrob Agents Chemother 1985; 28: 842-44.
SiR,—Dr Cain and Dr O’Connor and Dr Bates and colleagues’
implicate ciprofloxacin as an inciting agent in patients with pseudomembranous colitis and "superinfection" due to Clostridium difficile. Cain and O’Connor’s patient with pseudomembranous colitis had also received co-trimoxazole five weeks before presenting with diarrhoea. In our experience1 co-trimoxazole is more likely than ciprofloxacin to induce C difficile-associated disease. We have assessed the incidence of C difficile-associated diarrhoea in 213 patients on ciprofloxacin monotherapy. Of these, 29 were given ciprofloxacin for diarrhoea and a further 15 had loose stools during treatment. Stools from these 43 patients were examined for C difficile on at least one occasion and were negative. Of the remaining 169 patients without diarrheoa 73 were investigated for the presence of C difficile, with negative results. These data are consistent with our findings with an in vitro test-tube model of C difficile infection2 in which C difficile did not proliferate in the presence of ciprofloxacin. With respect to the in-vitro susceptibility of C difficile to ciprofloxacin, we have examined 205 strains of C difficile with an agar dilution technique. Minimum inhibitory concentrations of ciprofloxacin ranged from 8-32 mg/1, with 90% of strains inhibited by 16 mg/1. If Cain and O’Connor used a 5-g ciprofloxacin disc in their disc diffusion susceptibility test then, according to Barry and colleagues’3 criteria, all strains of C difficile would be resistant to ciprofloxacin. These criteria, however, relate to expected blood concentrations and might be inappropriate since ciprofloxacin concentrations in the gastrointestinal tract can reach 2220 Ilgfg.4 In addition, despite these high levels, quinolones have a small effect on reports
anaerobic gut florae Bates and colleagues and Hillman et alb describe patients with salmonella gastroenteritis in whom C difficile cytotoxin was subsequently detected. Both reports attribute the presence of C difficile to the ciprofloxacin used to treat enteric salmonellosis and ignore other plausible explanations. It is well recognised that any change in the normal bacterial faecal flora, due to microbial treatment or enteric infections like salmonellosis, can predispose a patient to colonisation (as in Bates and colleagues’ patients) or infection (as in the patient described by Hillman et all) with C difficile. 7.8 Although we agree with Bates and colleagues that symptom-free excreters of C difficile should not be ignored because they might be a
presented shows that the results obtained from airborne sampling are far from repeatable: fig 1 shows a similar ranking of repeat samples, but all are about 60% lower. A glaring omission is that mattress dust, the richest source of mite allergen, was not sampled. Despite the limitations of measuring floor dust Price et al
evidence
found a correlation between this measure and sensitisation. The level of 2 ug Der p 1/g proposed2 for sensitisation to mites is a working value for which there is increasing epidemiological data. The lower level of 05 )g/g that Price et al found may reflect this threshold when mattress dust is not assayed. There are also two areas of misinterpretation of previous work.3 .3 Price et al claim that particles 10 Etm or more in diameter cannot penetrate an infant’s airway. Increasing particle size simply reduces the percentage that enters the lung,4,5 and we know of no evidence that particles of this size are never inhaled. Price et al also say sampling rates of 20 1/min clear allergen from domestic air. This sampling rate is similar to the minute volume of an adult. The total volume of air sampled in our 1981 study3 was 400 litres, very similar to the total volume sampled in Price’s paper, and less than 10% of the volume of the rooms studied. Reservoir measurements have proved to be both a valid index of exposure6,7 and robust. Sampling methods, including airborne allergen measurements, were considered by two international workshops/,8 and reservoir measurements were endorsed as being relevant and the most practicable. A prospective study of allergen exposure based on reservoir measurements has been completed in the UK and there was a significant relation between exposure in infancy and childhood asthma.9 If airborne sampling is undertaken in future epidemiological studies, floor and mattress dust samples should also be obtained. Division of Allergy and Clinical Immunology, University of Virginia, Charlottesville, Virginia 22908, USA
RICHARD SPORIK MARTIN CHAPMAN THOMAS PLATTS-MILLS
Chapman MD, Heymann PW, Luczynska CM. Measurements of airborne allergen using immunoassays. Immunol Allergy Clin N Am 1989, 9: 269-83. 2. Anon Report of an international workshop Dust mite allergens and asthma. a worldwide problem J Allergy Clin Immunol 1989; 83: 416-27. 3. Tovey ER, Chapman MD, Wells CW, Platts-Mills TAE. The distribution of dust mite allergen m the houses of patients with asthma Am Rev Respir Dis 1981; 124: 630-35 4. Svartengren M, Falk R, Linnman L, et al Deposition of large particles in human lung Exp Lung Res 1987, 12: 75-88. 5. Harper GJ, Morton JD. The respiratory retention of bacterial aerosols: experiments with radioactive sports. J Hyg 1953, 51: 372-85. 6. Lau S, Falkenhorst G, Weber A, et al. High mite-allergen exposure increases the nsk of sensitisation m atopic children and young adults. J Allergy Clin Immunol 1989; 84: 718-25 7 Charpin D, Birnbaum J, Haddie E, Genard G, Toumi M, Vervolet D. Attitude and allergy to house dust mites: an epidemiological study in primary school children. J Allergy Clin Immunol 1990, 85: 185 (abstr) 8 Second International Workshop on Dust Mite Allergens and Asthma (Minster Lovell, 1. Platts-Mills TAE,
9.
Oxon, September, 1990). Sporik R, Holgate ST, Platts-Mills RAE, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood—a prospective study. N Engl J Med 1990, 323: 502-07.
SIR,-Dr Price and colleagues found no correlation between floor dust levels and airborne levels of mite allergens.’ This led to the conclusion that air sampling should be used to assess inhaled allergen exposure. As Price et al pointed out, asthma is triggered by the airborne allergens in the domestic environment which contain, besides mite allergens, airborne moulds that have been implicated in allergic asthma.2 We have measured airborne mould levels in the homes of asthmatic patients3 and found results consistent with Price and colleagues’ study. There was no correlation between dust mould and airborne mould concentrations, and neither wall humidity nor indoor temperature had any effect on dust or airborne moulds. Price et al conclude that furnishings, ventilation, and other factors affecting airborne allergen levels must be taken into account in the assessment of exposure. In our study, although airborne mould concentrations did not depend on the floor types, indoor mould concentrations were influenced by the type of housing. Levels of airborne moulds were higher in recent houses than in old ones, and in collective housing than in individual homes (especially
in winter, a poor season for moulds). Poor ventilation and insulation material may be important factors that increase the level of moulds exposure. In view of Price and colleagues’ hypothesis, this could also be true for airborne mite allergens. J. M. TUNON DE LARA Department of Respiratory Disease, R. MARTHAN Hôpital Haut-Lévêque, A. TAYTARD CHU Bordeaux, F-33604 Pessac, France 1 2
Price JA, Pollock I, Little SA, Longbottom JL, Warner JO. Measurements of airborne mite allergen in homes of asthmatic children Lancet 1990; 336: 895-97. Salvaggio J, Aukrust L. Mould induced asthma J Allergy Clin Immunol 1981; 68:
327-46. 3. Tunon de Lara JM, Tessier JF, Lafond Grellety J, patients homes Aerobiologia 1990, 6: 98-101.
et
al. Indoor moulds in asthmatic
SiR,-What is in the carpet is certainly not as important as what is in the air. In 1976 we demonstrated in sensitive individuals a significant correlation between the concentration of particles in the inhaled air and a decrease in peak flow, but only for particle sizes below 2 pm.1 The reduction in peak flow was significantly greater only at times when the house was being swept or a vacuum cleaner was being used. The inference is that the carpet may be safe, whatever its content or composition, provided it is not being cleaned. Housedust-sensitive asthmatic children should stay away whilst the house is being cleaned, and for at least an hour afterwards. T. D. PRESTON L. SINCLAIR
Westminster Hospital. London SW1 P 2AP, UK
1. Clark RP, Preston TD, Gordon-Nesbitt DC, Malka
S, Sinclair L. The size of airborne dust particles precipitating bronchospasm in house dust sensitive children J Hyg (Camb) 1976; 77: 321-25.
Cyclophosphamide for chronic relapsing thrombotic thrombocytopenic purpura SIR,- If undiagnosed and untreated thrombotic thrombocytopenic (TTP) runs a fulminant course. Early appropriate plasma therapy and plasmapheresis reduces death rates in acute TTP, but purpura
for chronic relapsing TTP can pose difficulties. Dr Bird and her colleagues (Sept 1, p 565) report a 26-year-old woman whose chronic TTP responded well to cyclophosphamide (with other therapeutic measures). We describe a patient in whom cyclophosphamide proved beneficial in a somewhat similar clinical treatment
setting. A 53-year-old
presented in 1987 with progressive megakaryocytic thrombocytopenia (platelets less than 109/1), indirect hyperbilirubinaemia, uraemia, and non-immune haemolytic anaemia with fragmented red blood cells. Plasma values for von Willebrand factor antigen, P-thromboglobulin, and thromboxane-B2 were high, whereas prostacyclin metabolite (6-keto-prostaglandin-F) proved to be undetectable in plasma and in clotted whole blood. The presence of cytotoxic endothelial antibodies was also verified. She was immediately given fresh-frozen plasma with striking improvement, soon followed by serious relapse. Plasmapheresis was effective during the first relapse but not in the second, and splenectomy was therefore undertaken. The appearance of Howell-Jolly bodies post splenectomy indicated active splenic-tissue remnants. After splenectomy the relapsing pattern of the disorder did not change much, but thrombocytopenia, haemolysis, and renal insufficiency were less severe. Aspirin did not ameliorate her symptoms. In 1988 malignant lymphoma of T-cell origin was suspected (13-16 x 109/1 lymphocytes, 50-70% lymphocellular bone-marrow infiltration, Combined chemotherapy presence of T-cell markers). (cyclophosphamide, corticosteroid, and vincristine) resulted in long-term improvement of TTP-related symptoms, but vinca alkaloids were stopped later because of neurotoxicity. Since then she has received cyclophosphamide (brief infusion of 600-800 mg, sometimes repeated after a week) which was effective in achieving remissions on five occasions, remission usually lasting for 4-6
confusion,
months.
coma,
woman
severe
1509
Our patient provides further evidence that cyclophosphamide be regarded as a valuable therapeutic option in chronic relapsing TTP. Our patient probably also had an associated disease (T-cell lymphoma). Nonetheless cyclophosphamide infusions might be of therapeutic value in acute episodes of chronic relapsing TTP and in lengthening of otherwise short remission periods. can
Department of Medicine, University Medical School,
2nd
H-4012 Debrecen,
MIKLOS UDVARDY KALMAN RAK
Hungary
Ciprofloxacin
and
pseudomembranous
colitis SIR,-Dr Cain and Dr O’Connor (Oct 13, p 946) raise the spectre of ciprofloxacin being implicated in pseudomembranous colitis (PMC), and they advise caution in the use of this agent in acute diarrhoea. Ciprofloxacin’s activity against most anaerobes is very limited-indeed, the 90% inhibitory concentration (MIC) for ciprofloxacin against Clostridium difficile is 32 mg/1.1 Even though the faecal levels achieved exceed 32 mg/1 the loss of bactericidal activity under anaerobic conditions2 leads to the virtual lack of effect on the anaerobic faecal flora.3 Pecquet et aP observed no overgrowth or adverse effects with C difficile during their study. When the normal anaerobic intestinal flora is much reduced the protective factor against C difficile overgrowth is removed.’ During ciprofloxacin therapy only the Enterobacteriaceae are greatly reduced, changes in other genera being negligible. Antimicrobial agents most frequently associated with PMC are those with strong activity against anaerobes (eg, penicillins, cephalosporins, and clindamycin). Metronidazole and vancomycin have been implicated in relapses,s,6 even though they have been used successfully to treat C difficile infection. From spontaneous reports and from clinical trial data 14 cases of PMC involving ciprofloxacin have been recorded. However, over 40 million patients worldwide have been treated with this drug over the past 5 years, and in half the PMC cases the patient was taking or had recently received other antimicrobial agents. Causality is thus difficult to prove. To recommend, in cases of acute non-bloody diarrhoea, screening for ciprofloxacin-resistant C difficile would impose on microbiology laboratories a huge workload that might be irrelevant in view of the tenuous evidence for a role of ciprofloxacin in PMC. Research and
Development Department, Bayer UK, Newbury RG13 1JA, UK 1.
B. J. O’KEEFFE G. S. TILLOTSON
Barry AL. In-vitro activity of the fluoroquinolone compounds. Antimicrob News 1988;
5: 69-76. 2. Smith JT, Lewin CS. Chemistry and mechanisms of action of the quinolone antibacterials. In: Andriole VT, ed. The quinolones. London: Academic Press, 1988: 23-82. 3. Pecquet S, Ravoire S, Andremont A. Faecal excretion of ciprofloxacin after a single oral dose and its effect on faecal bacteria in healthy volunteers. J Antimicrob
Chemother 1990, 26: 125-29. Fekty R, Kim K-H, Batts DH, et al Studies on the epidemiology of antibiotic associated Clostridium difficile colitis. Am J Clin Nutr 1980; 33: 2527-32. 5. George WL, Volpicelli NA, Stiner DB, et al Relapse of pseudomembranous colitis after vancomycin therapy. N Engl J Med 1975; 30: 414-15. 6. George WL, Rolfe RD, Fmegold SM. Clostridium difficile and its cytotoxin in faeces of
4.
patients with antimicrobial agent associated diarrhoea and miscellaneous conditions. J Clin Microbiol 1982; 15: 1049-53.
SIR,-Dr Cain and Dr O’Connor mention that quinolones have not implicated in pseudomembranous colitis. Although this is true of ciprofloxacin, ofloxacin has been associated with pseudomembranous colitis in one case reported in Englishlanguage publications.We have recently seen a 72-year-old patient treated with maintenance peritoneal dialysis because of analgesic nephropathy. She received a 2-week course of ofloxacin, three months before the onset of colitis, for a coliform bladder infection. Bladder polyps were found, and before a planned cystoscopic resection had a right been
cerebral infarct. She was treated with phenoxymethylpenicillin orally for 1 week for a suspected aspiration pneumonia (within 1 week of stopping ofloxacin). 10 weeks before the onset of colitis she
received one dose of intravenous (iv) vancomycin 1 g together with iv netilmicin 200 mg, after an arteriovenous shunt. A second course of ofloxacin was given for cough with green sputum and fever. 2 days later she had abdominal pain, diarrhoea, and toxic clonic dilatation, and stool specimens were positive for Clostridium difficile and toxin. She was treated with vancomycin and metronidazole, but had a prolonged ileus and died 2 weeks later with a left cerebral infarct. What worries us especially about this case is the rapid onset of colitis shortly after starting the second course of ofloxacin. Pseudomembranous colitis is recognised in uraemia, but the suppressive role of antibiotics on native resistance to C difficile colonisation is presumed to be of pathogenic importance 2 The rapid effect of ofloxacin on the gut flora of a patient being treated with antibiotics could have led to an especially speedy onset of colitis. In view of the low in-vitro sensitivity of C difficile to several quinolonesthese drugs should not be used in pseudomembranous colitis. Repeated use in patients with diarrhoea should also be avoided if possible. S. L. CHEW Department of Nephrological Hypertension, R. DAELEMANS A Z Stuivenberg, B 2060 Antwerp, Belgium R. L. LINS 1. Dan M, Samra Z. Clostridium difficile colitis associated with ofloxacin therapy.
Am J
Med 1989; 87: 479. 2 Larson HE. Botulism, gas gangrene and clostridial gastrointestinal infections. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine. Oxford: OUP, 1987: 5.270-77. 3. Chow AW, Cheng N, Bartlett KH. In vitro susceptibility of Clostridium difficile to new beta-lactam and quinolone antibodies. Antimicrob Agents Chemother 1985; 28: 842-44.
SiR,—Dr Cain and Dr O’Connor and Dr Bates and colleagues’
implicate ciprofloxacin as an inciting agent in patients with pseudomembranous colitis and "superinfection" due to Clostridium difficile. Cain and O’Connor’s patient with pseudomembranous colitis had also received co-trimoxazole five weeks before presenting with diarrhoea. In our experience1 co-trimoxazole is more likely than ciprofloxacin to induce C difficile-associated disease. We have assessed the incidence of C difficile-associated diarrhoea in 213 patients on ciprofloxacin monotherapy. Of these, 29 were given ciprofloxacin for diarrhoea and a further 15 had loose stools during treatment. Stools from these 43 patients were examined for C difficile on at least one occasion and were negative. Of the remaining 169 patients without diarrheoa 73 were investigated for the presence of C difficile, with negative results. These data are consistent with our findings with an in vitro test-tube model of C difficile infection2 in which C difficile did not proliferate in the presence of ciprofloxacin. With respect to the in-vitro susceptibility of C difficile to ciprofloxacin, we have examined 205 strains of C difficile with an agar dilution technique. Minimum inhibitory concentrations of ciprofloxacin ranged from 8-32 mg/1, with 90% of strains inhibited by 16 mg/1. If Cain and O’Connor used a 5-g ciprofloxacin disc in their disc diffusion susceptibility test then, according to Barry and colleagues’3 criteria, all strains of C difficile would be resistant to ciprofloxacin. These criteria, however, relate to expected blood concentrations and might be inappropriate since ciprofloxacin concentrations in the gastrointestinal tract can reach 2220 Ilgfg.4 In addition, despite these high levels, quinolones have a small effect on reports
anaerobic gut florae Bates and colleagues and Hillman et alb describe patients with salmonella gastroenteritis in whom C difficile cytotoxin was subsequently detected. Both reports attribute the presence of C difficile to the ciprofloxacin used to treat enteric salmonellosis and ignore other plausible explanations. It is well recognised that any change in the normal bacterial faecal flora, due to microbial treatment or enteric infections like salmonellosis, can predispose a patient to colonisation (as in Bates and colleagues’ patients) or infection (as in the patient described by Hillman et all) with C difficile. 7.8 Although we agree with Bates and colleagues that symptom-free excreters of C difficile should not be ignored because they might be a
