337
gia, abdominal pain, and glomerulonephritis.2,3Such patients usually have complement disorders and raised erythrocyte-sedimentation rates. We found no haematological abnormalities, serum cryoglobulins, or evidence of systemic disease in any of our patients whose serum-complement (C3) levels were normal (six patients) or slightly raised (two patients). The presence of neutrophils and eosinophils in the inflammatory infiltrate after multiple cold challenge is of especial interest because chemotactic factors for eosinophils4 and neutrophils’ have previously been found in venous blood from urticated skin following cold challenge in cold urticaria. Cold urticaria is an expression of an immediate hypersensitivity reaction in which histamine is thought to be the major inflammatory mediator.6 Vasculitis has not previously been described as a feature of essential acquired cold urticaria, so its arousal by repeated cold challenge in our patients presumably reflects sustained injury to small cutaneous blood vessels. Whether this injury is due mainly to pharmacological or to immunological processes or to a mixture of both needs further clarification. R. A. J. EADY M. W. GREAVES
Institute of Dermatology, London E9 6BX
MECILLINAM
SIR,-Our experience of the activity of mecillinam against gram-negative bacilli has been less favourable than that of Dr Chattopadhyay and Dr Thomas (Jan. 28, p. 214). Our methods were very similar, except for the use of ’Iso-sensitest’ agar (Oxoid) and a standardised inoculum of 105 colony-forming units of bacteria. When mecillinam was tested against ampicillin (and amoxycillin) resistant enterobacteria its activity was comparable with that of carbenicillin, but it was less active than seven cephalosporins and cefoxitin (see table). We studied 87 recent isolates from urines and 11 from wounds; all were from different patients with no epidemiological connection. We did not observe the bimodal distribution of mecillinam susceptibilities reported by Chattopadhyay and Thomas who IN-VITRO SUSCEPTIBILITY OF
98
the antibiotic’ mecillinam (carbenicillin and cephaloridine, cephalothin, cephazolin, and cefamandole) was partially inac-
tivated, and all six antibiotics were very vulnerable to P4actamase preparations, including the clinically important enzyme from Escherichia coli (TEM)2 This susceptibility can be correlated with a large-inoculum effect, which is most striking with mecillinam. Enzyme susceptibility and inoculum effect were minimal with cephradine, cefuroxime, and cefoxitin, while cephalexin gave intermediate values. Despite our disappointment with the antibacterial activity of mecillinam, and its vulnerability to &bgr;-lactamases, the antibiotic’s unusual mode of action, discussed in your editorial of Feb. 4 (p. 252), is of great interest. Unlike other p-lactam agents, it converts gram-negative rods to large osmotically stable round or oval cells, over a wide range of concentrations. This effect is probably due-at least in E.coli-to the affinity of the antibiotic for the type 2 "penicillin-binding protein" only, which seems to have the extraordinarily specific function of producing transpeptidation (a final stage in cell-wall synthesis) at the "corners" of the bacterial cell. This uniquely restricted effect of mecillinam is complementary to the action of other p-lactam antibiotics that inhibit cell-wall synthesis at different sites. On this basis, the combination of mecillinam with other p-lactam agents would be expected to be synergistic, and indeed this is often the case both in vitro and in vivo, notably with amoxycillin or cephradine.4 There are, nevertheless, important economic implications if combinations of expensive antibiotics come into widespread use in the future. Gifts of mecillinam, cefoxitin, cefuroxime, and cefamandole were received from Leo Laboratories, Merck Sharp and Dohme, Glaxo Laboratories, and Eli Lilly and Co., respectively.
Department of Bacteriology, Westminster Medical School, London SW1P 2AR
M. BAKHTIAR S. SELWYN
*** A line was dropped from our mecillinam editorial last week (restored in American edition). The second sentence was meant to say: "Other penicillins are synthesised from aminopenicillanic acid; mecillinam is derived from amidinopenicillanic acid, and its antibacterial spectrum is different."—ED. L
AMPICILLIN-RESISTANT
GRAM-NEGATIVE BACILLI TO BETA-LACTAM ANTIBIOTICS
BACTERIAL OVERGROWTH SYNDROME AFTER ACUTE NONSPECIFIC DIARRHŒA
SIR,-In support of the findings of Roberts
et
a1.5
we
have
recently patients (male aged 49, female aged 67) with bacterial overgrowth syndrome following acute nonspecific diarrhoea. Each had travelled to Mexico where they had an acute episode of watery diarrhoea (8-10 bowel movements/day) which lasted for five days and then became chronic (3-5 unformed stools/day and weight loss). The patients were seen by us 1 month and 3 months respectively after the initial episode. There was no anatomical abnormality. Infectious diarrhoea was ruled out because stool culture for Shigella, Salmonella, enterotoxigenic Eschericia coli (heat-labile or heat-stabletoxin-producing) and Vibrio parahcemolyticus was negative. No ova or parasites were seen in the stool preparation. There was no significant antibody titre to heat-labile toxin of enteroseen two
* Susceptible
to
10 mg/l of antibiotic (except for carbenicillin 50
mg/1). t Results with cephalothin, cephalexin, cephradine, cephazolin, cefuroxime, cefoxitin, and cefamandole were similar in these conventional tests.
found minimum inhibitory concentrations (M.!.c.s) either between 0.1and 1 mg/1 or 100 mg/1 and above. When test systems were used which allowed bacteria to enter the logarithmic growth phase and produce p4actamases before encountering 2. Soter, N. A., Austen, K. F., Gigli, I. J. invest. Derm. 1974, 63, 485. 3. Soter, N. A. New Engl. J. Med. 1977, 296, 1440. 4. Soter, N. A., Wasserman, S. I., Austen, K. F. ibid. 1976, 294, 698. 5. Wasserman, S. I., Soter, N. A., Center, D. M., Austen, K. F. J. clin. Invest.
1977, 60, 189. 6. Kaplan, A. P., Gray, L., Shaff, R. E., Horakova, Z., Beaven, M. A. Allergy clin. Immun. 1975, 55, 394.
E. coli. colonisation factor of E. coli H-10407 was Duodenal biopsy was normal and Giardia lamblia was absent both by direct observation and by routine histology. In duodenal aspirates, a pure culture of Pseudomonas (108 colonies/ml) was recovered from patient 1 and Enterobacter (106 colonies/ml) and a-Streptococcus (102 colonies/ml) from patient 2.
toxigenic negative.
117 were P. mirabilis.
J.,
1. Bakhtiar, M., Selwyn, S. Proc. 10th int. Chemother. Congr. (in the 2. Selwyn, S. J. antimicrob. Chemother. 1977, 3, 161. 3. Spratt, B. G. ibid. 1977, 3, suppl. B, p. 13. 4. Kerry, D. W., Hamilton-Miller, J. M. T., Brumfitt, W. ibid. 1977, 3,
B, p. 53. 5. Roberts, S. H., James, O., Jarvis, E. H. Lancet, 1977, ii, 1193.
press). Suppl.
338 After treatment with tetracycline for 7 days, both patients recovered fully. The history of acute diarrhoea before the onset of malabsorption syndrome in our patients and in three out of five of the patients of Roberts et al. suggests that this is probably an important factor in a predisposed host for the development of bacterial malabsorption syndrome. We feel this may be important and see no reason why it should be restricted to adults. of Texas Health Science Center, Houston, Texas 77025, U.S.A.
University
GUILLERMO M. RUIZ-PALACIOS HERBERT L. DUPONT
BACTERIAL OVERGROWTH SYNDROME WITHOUT BLIND LOOP
SIR,-Dr Roberts and his colleagues’ make the important
point that malabsorption due to bacterial contamination of the small bowel can occur in the absence of a demonstrable anatomical abnormality. Their claim that this had not previously been described must, however, be refuted. In 1971 I suggested that the term "contaminated small bowel syndrome" should be used rather than the earlier term "blind loop syndrome", for this very reason.2 Examples include cholangitis where the infected biliary tree acts as a reservoir for bacteria to contaminate the upper gut,3 infants with temporary monosaccharide malabsorption,4 and infants and children with malnutrition.5,6 Princess Margaret Children’s Medical Research Foundation. Perth, Western Australia 6001
MICHAEL GRACEY
SIR,-We also have seen patients with bacterial contamination of the small bowel but no demonstrable anatomical sump.7 Five patients had a specific motor disorder of stomach and small intestine, characterised by absence of the cyclically recurring fronts of propulsive motor activity that are found in all normal individuals. All five had evidence of jejunal bacterial overgrowth, with abnormal 14C-glycocholic-acid breath tests that returned to normal after a 5-day course of antibiotics. A blind loop or organic stenosis was not demonstrable, but one patient had systemic sclerosis and dilated jejunal loops. Although we cannot be certain that the motility disorder caused the bacterial overgrowth in these patients, it might be worth looking for this motility disorder in elderly patients with the syndrome described by Roberts et al. Department of Medical Research, University of Leuven, St. Rafaël, B-3000 Leuven,
Belgium
G. VANTRAPPEN
WILL THE REAL CLOSTRIDIUM SPECIES RESPONSIBLE FOR ANTIBIOTIC-ASSOCIATED COLITIS PLEASE STEP FORWARD?
SIR,-Two recent Lancet papers have noted that stools from patients with antibiotic-associated colitis contain a toxin which is cytopathic in tissue culture.8,9 The cytopathic effects of the toxin were neutralised with Clostridium sordellii antitoxin. The conclusion is that Cl,. sordellii is responsible for antibiotic-associated colitis. 1. 2. 3. 4. 5.
Roberts, S. H., James, O., Jarvis, G. H. Lancet, 1977, ii, 1193. Gracey, M. Gut, 1971, 12, 403. Scott, A. J., Khan, G. A. ibid. 1968, 9, 187. Gracey, M., Burke, V., Anderson, C. M. Lancet, 1969, ii, 384. Gracey, M., Suharjono, Sunoto, Stone, D. E. Am. J. clin. Nutr. 1973, 26,
1170. 6. Heyworth, B., Brown, J. Archs. Dis. Childh. 1975, 50, 27. 7. Vantrappen, G., Janssens, J., Hellemans, J., Ghoos, Y. J. clin. Invest.
59, 1158. 8. Rifkin, G. D., Fekety, F. R., Silva, J. Jr. Lancet, 9. Larson, H. E., Price, A. B. ibid. p. 1312.
1977, ii, 1103.
1977,
Similar results have been noted in our laboratory using Cl. sordellii antitoxin to neutralise colitis toxin. However, we have been reluctant to ascribe a pathogenic role to this organism because Cl. sordellii has not been recovered in stool cultures by us or by others,8,9 because intracoccal injections of reference strains of Cl. sordellii kill hamsters but necropsies reveal no intestinal lesions, and because the cell-free supernatant of toxinproducing Cl. sordellii strains fail to produce cytotoxicity in tissue culture. Wel0,l1 have found another clostridial species which seems to satisfy these criteria. Cultures of stools from patients with antibiotic-associated colitis yielded Cl. difficile, an organism which is rarely encountered in the normal flora of healthy persons. Broth cultures of these isolates injected intracxcally into hamsters caused an enterocolitis which simulates the anatomical features of the disease encountered clinically. Furthermore, the cell-free supernatant of the Cl. difficile isolates are cytopathic in tissue culture and cytotoxicity is neutralised when the broth supernatants of these strains are mixed with either gasgangrene polyvalent antitoxin or Cl. sordellii antitoxin.’ Our conclusion is that Cl. sordellii antitoxin does indeed neutralise the toxin found in stools from patients with antibiotic-associated colitis. However, this may represent antigenic cross-reactivity between clostridial toxins. Other clostridial species may cause this disease, but the weight of evidence strongly supports the pathogenic role of Cl. difficile. Infectious Disease Research Laboratory, Boston Veterans Administration Hospital, and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, U.S.A.
JOHN G. BARTLETT TEWEN CHANG ANDREW B. ONDERDONK
TREATMENT OF ANTIBIOTIC-INDUCED COLITIS BY METRONIDAZOLE
SIR,-Rifkin et al.’ and Dr Modigliani and Dr Delchier (Jan. 14, p. 97) described cases of antibiotic-induced colitis which responded rapidly to oral vancomycin. Your editorial2 prompted us to try metronidazole therapy in a case of severe ampicillin-induced colitis. The patient was a 27-year-old woman, without a history of gastrointestinal disease. 3 days before becoming ill, she had finished a 7-day course of ampicillin (2g/day) for bronchitis. She had colicky abdominal pain, frequent bowel movements, vomiting, and fever (40 °C), which were followed by asthenia, anorexia and mild weight loss. Abdominal signs and fever persisted for 10 days before she was admitted. On examination, the patient was moderately dehydrated and had a distended, tender abdomen. Serum-sodium was 125 mmol/l, hxmoglobin was 9 g/dl, and serum-albumin was 2.2 g/dl. Proctosigmoidoscopy showed numerous yellow-white plaques with intervening normal mucosa. Biopsy confirmed the diagnosis of pseudomembranous colitis. Barium enema showed that the whole colonic wall had a thumb-print pattern. Qualitative stool culture revealed Clostridium perfringens, Cl. butyricum, Bacteroides species, and normal aerobic flora. The patient’s general condition improved after 5 days water-electrolyte replacement and low-residue diet, but diarrhoea persisted with 8-10 liquid, malodorous stools per day. After metronidazole (1-3 g/day) was given, this improved to 3,2, and 1 soft stools/day after 24 h, 48 h, and 72 h treatment, respectively. Proctosigmoidoscopy done 7 days later showed a normal mucosa, confirmed by biopsy, and a second barium enema showed a normal mucosal pattern with only light residual motor disturbances. Metronidazole was 10. Bartlett, J. G., Change, T. W., Gurwith, M., Gorbach, S. L., Onderdonk, A. B. New Engl. J. Med. (in the press). 11. Bartlett, J. G., Onderdonk, A. B., Cisneros, R. L., Kasper, D. L. J. infect. Dis. 1977, 136, 701. 1. Rifkin, G. D., Fekety, F. R., Silva, J., Sack, R. B. Lancet, 1977, ii, 1103.
2. ibid. p. 1113.
gia, abdominal pain, and glomerulonephritis.2,3Such patients usually have complement disorders and raised erythrocyte-sedimentation rates. We found no haematological abnormalities, serum cryoglobulins, or evidence of systemic disease in any of our patients whose serum-complement (C3) levels were normal (six patients) or slightly raised (two patients). The presence of neutrophils and eosinophils in the inflammatory infiltrate after multiple cold challenge is of especial interest because chemotactic factors for eosinophils4 and neutrophils’ have previously been found in venous blood from urticated skin following cold challenge in cold urticaria. Cold urticaria is an expression of an immediate hypersensitivity reaction in which histamine is thought to be the major inflammatory mediator.6 Vasculitis has not previously been described as a feature of essential acquired cold urticaria, so its arousal by repeated cold challenge in our patients presumably reflects sustained injury to small cutaneous blood vessels. Whether this injury is due mainly to pharmacological or to immunological processes or to a mixture of both needs further clarification. R. A. J. EADY M. W. GREAVES
Institute of Dermatology, London E9 6BX
MECILLINAM
SIR,-Our experience of the activity of mecillinam against gram-negative bacilli has been less favourable than that of Dr Chattopadhyay and Dr Thomas (Jan. 28, p. 214). Our methods were very similar, except for the use of ’Iso-sensitest’ agar (Oxoid) and a standardised inoculum of 105 colony-forming units of bacteria. When mecillinam was tested against ampicillin (and amoxycillin) resistant enterobacteria its activity was comparable with that of carbenicillin, but it was less active than seven cephalosporins and cefoxitin (see table). We studied 87 recent isolates from urines and 11 from wounds; all were from different patients with no epidemiological connection. We did not observe the bimodal distribution of mecillinam susceptibilities reported by Chattopadhyay and Thomas who IN-VITRO SUSCEPTIBILITY OF
98
the antibiotic’ mecillinam (carbenicillin and cephaloridine, cephalothin, cephazolin, and cefamandole) was partially inac-
tivated, and all six antibiotics were very vulnerable to P4actamase preparations, including the clinically important enzyme from Escherichia coli (TEM)2 This susceptibility can be correlated with a large-inoculum effect, which is most striking with mecillinam. Enzyme susceptibility and inoculum effect were minimal with cephradine, cefuroxime, and cefoxitin, while cephalexin gave intermediate values. Despite our disappointment with the antibacterial activity of mecillinam, and its vulnerability to &bgr;-lactamases, the antibiotic’s unusual mode of action, discussed in your editorial of Feb. 4 (p. 252), is of great interest. Unlike other p-lactam agents, it converts gram-negative rods to large osmotically stable round or oval cells, over a wide range of concentrations. This effect is probably due-at least in E.coli-to the affinity of the antibiotic for the type 2 "penicillin-binding protein" only, which seems to have the extraordinarily specific function of producing transpeptidation (a final stage in cell-wall synthesis) at the "corners" of the bacterial cell. This uniquely restricted effect of mecillinam is complementary to the action of other p-lactam antibiotics that inhibit cell-wall synthesis at different sites. On this basis, the combination of mecillinam with other p-lactam agents would be expected to be synergistic, and indeed this is often the case both in vitro and in vivo, notably with amoxycillin or cephradine.4 There are, nevertheless, important economic implications if combinations of expensive antibiotics come into widespread use in the future. Gifts of mecillinam, cefoxitin, cefuroxime, and cefamandole were received from Leo Laboratories, Merck Sharp and Dohme, Glaxo Laboratories, and Eli Lilly and Co., respectively.
Department of Bacteriology, Westminster Medical School, London SW1P 2AR
M. BAKHTIAR S. SELWYN
*** A line was dropped from our mecillinam editorial last week (restored in American edition). The second sentence was meant to say: "Other penicillins are synthesised from aminopenicillanic acid; mecillinam is derived from amidinopenicillanic acid, and its antibacterial spectrum is different."—ED. L
AMPICILLIN-RESISTANT
GRAM-NEGATIVE BACILLI TO BETA-LACTAM ANTIBIOTICS
BACTERIAL OVERGROWTH SYNDROME AFTER ACUTE NONSPECIFIC DIARRHŒA
SIR,-In support of the findings of Roberts
et
a1.5
we
have
recently patients (male aged 49, female aged 67) with bacterial overgrowth syndrome following acute nonspecific diarrhoea. Each had travelled to Mexico where they had an acute episode of watery diarrhoea (8-10 bowel movements/day) which lasted for five days and then became chronic (3-5 unformed stools/day and weight loss). The patients were seen by us 1 month and 3 months respectively after the initial episode. There was no anatomical abnormality. Infectious diarrhoea was ruled out because stool culture for Shigella, Salmonella, enterotoxigenic Eschericia coli (heat-labile or heat-stabletoxin-producing) and Vibrio parahcemolyticus was negative. No ova or parasites were seen in the stool preparation. There was no significant antibody titre to heat-labile toxin of enteroseen two
* Susceptible
to
10 mg/l of antibiotic (except for carbenicillin 50
mg/1). t Results with cephalothin, cephalexin, cephradine, cephazolin, cefuroxime, cefoxitin, and cefamandole were similar in these conventional tests.
found minimum inhibitory concentrations (M.!.c.s) either between 0.1and 1 mg/1 or 100 mg/1 and above. When test systems were used which allowed bacteria to enter the logarithmic growth phase and produce p4actamases before encountering 2. Soter, N. A., Austen, K. F., Gigli, I. J. invest. Derm. 1974, 63, 485. 3. Soter, N. A. New Engl. J. Med. 1977, 296, 1440. 4. Soter, N. A., Wasserman, S. I., Austen, K. F. ibid. 1976, 294, 698. 5. Wasserman, S. I., Soter, N. A., Center, D. M., Austen, K. F. J. clin. Invest.
1977, 60, 189. 6. Kaplan, A. P., Gray, L., Shaff, R. E., Horakova, Z., Beaven, M. A. Allergy clin. Immun. 1975, 55, 394.
E. coli. colonisation factor of E. coli H-10407 was Duodenal biopsy was normal and Giardia lamblia was absent both by direct observation and by routine histology. In duodenal aspirates, a pure culture of Pseudomonas (108 colonies/ml) was recovered from patient 1 and Enterobacter (106 colonies/ml) and a-Streptococcus (102 colonies/ml) from patient 2.
toxigenic negative.
117 were P. mirabilis.
J.,
1. Bakhtiar, M., Selwyn, S. Proc. 10th int. Chemother. Congr. (in the 2. Selwyn, S. J. antimicrob. Chemother. 1977, 3, 161. 3. Spratt, B. G. ibid. 1977, 3, suppl. B, p. 13. 4. Kerry, D. W., Hamilton-Miller, J. M. T., Brumfitt, W. ibid. 1977, 3,
B, p. 53. 5. Roberts, S. H., James, O., Jarvis, E. H. Lancet, 1977, ii, 1193.
press). Suppl.
338 After treatment with tetracycline for 7 days, both patients recovered fully. The history of acute diarrhoea before the onset of malabsorption syndrome in our patients and in three out of five of the patients of Roberts et al. suggests that this is probably an important factor in a predisposed host for the development of bacterial malabsorption syndrome. We feel this may be important and see no reason why it should be restricted to adults. of Texas Health Science Center, Houston, Texas 77025, U.S.A.
University
GUILLERMO M. RUIZ-PALACIOS HERBERT L. DUPONT
BACTERIAL OVERGROWTH SYNDROME WITHOUT BLIND LOOP
SIR,-Dr Roberts and his colleagues’ make the important
point that malabsorption due to bacterial contamination of the small bowel can occur in the absence of a demonstrable anatomical abnormality. Their claim that this had not previously been described must, however, be refuted. In 1971 I suggested that the term "contaminated small bowel syndrome" should be used rather than the earlier term "blind loop syndrome", for this very reason.2 Examples include cholangitis where the infected biliary tree acts as a reservoir for bacteria to contaminate the upper gut,3 infants with temporary monosaccharide malabsorption,4 and infants and children with malnutrition.5,6 Princess Margaret Children’s Medical Research Foundation. Perth, Western Australia 6001
MICHAEL GRACEY
SIR,-We also have seen patients with bacterial contamination of the small bowel but no demonstrable anatomical sump.7 Five patients had a specific motor disorder of stomach and small intestine, characterised by absence of the cyclically recurring fronts of propulsive motor activity that are found in all normal individuals. All five had evidence of jejunal bacterial overgrowth, with abnormal 14C-glycocholic-acid breath tests that returned to normal after a 5-day course of antibiotics. A blind loop or organic stenosis was not demonstrable, but one patient had systemic sclerosis and dilated jejunal loops. Although we cannot be certain that the motility disorder caused the bacterial overgrowth in these patients, it might be worth looking for this motility disorder in elderly patients with the syndrome described by Roberts et al. Department of Medical Research, University of Leuven, St. Rafaël, B-3000 Leuven,
Belgium
G. VANTRAPPEN
WILL THE REAL CLOSTRIDIUM SPECIES RESPONSIBLE FOR ANTIBIOTIC-ASSOCIATED COLITIS PLEASE STEP FORWARD?
SIR,-Two recent Lancet papers have noted that stools from patients with antibiotic-associated colitis contain a toxin which is cytopathic in tissue culture.8,9 The cytopathic effects of the toxin were neutralised with Clostridium sordellii antitoxin. The conclusion is that Cl,. sordellii is responsible for antibiotic-associated colitis. 1. 2. 3. 4. 5.
Roberts, S. H., James, O., Jarvis, G. H. Lancet, 1977, ii, 1193. Gracey, M. Gut, 1971, 12, 403. Scott, A. J., Khan, G. A. ibid. 1968, 9, 187. Gracey, M., Burke, V., Anderson, C. M. Lancet, 1969, ii, 384. Gracey, M., Suharjono, Sunoto, Stone, D. E. Am. J. clin. Nutr. 1973, 26,
1170. 6. Heyworth, B., Brown, J. Archs. Dis. Childh. 1975, 50, 27. 7. Vantrappen, G., Janssens, J., Hellemans, J., Ghoos, Y. J. clin. Invest.
59, 1158. 8. Rifkin, G. D., Fekety, F. R., Silva, J. Jr. Lancet, 9. Larson, H. E., Price, A. B. ibid. p. 1312.
1977, ii, 1103.
1977,
Similar results have been noted in our laboratory using Cl. sordellii antitoxin to neutralise colitis toxin. However, we have been reluctant to ascribe a pathogenic role to this organism because Cl. sordellii has not been recovered in stool cultures by us or by others,8,9 because intracoccal injections of reference strains of Cl. sordellii kill hamsters but necropsies reveal no intestinal lesions, and because the cell-free supernatant of toxinproducing Cl. sordellii strains fail to produce cytotoxicity in tissue culture. Wel0,l1 have found another clostridial species which seems to satisfy these criteria. Cultures of stools from patients with antibiotic-associated colitis yielded Cl. difficile, an organism which is rarely encountered in the normal flora of healthy persons. Broth cultures of these isolates injected intracxcally into hamsters caused an enterocolitis which simulates the anatomical features of the disease encountered clinically. Furthermore, the cell-free supernatant of the Cl. difficile isolates are cytopathic in tissue culture and cytotoxicity is neutralised when the broth supernatants of these strains are mixed with either gasgangrene polyvalent antitoxin or Cl. sordellii antitoxin.’ Our conclusion is that Cl. sordellii antitoxin does indeed neutralise the toxin found in stools from patients with antibiotic-associated colitis. However, this may represent antigenic cross-reactivity between clostridial toxins. Other clostridial species may cause this disease, but the weight of evidence strongly supports the pathogenic role of Cl. difficile. Infectious Disease Research Laboratory, Boston Veterans Administration Hospital, and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, U.S.A.
JOHN G. BARTLETT TEWEN CHANG ANDREW B. ONDERDONK
TREATMENT OF ANTIBIOTIC-INDUCED COLITIS BY METRONIDAZOLE
SIR,-Rifkin et al.’ and Dr Modigliani and Dr Delchier (Jan. 14, p. 97) described cases of antibiotic-induced colitis which responded rapidly to oral vancomycin. Your editorial2 prompted us to try metronidazole therapy in a case of severe ampicillin-induced colitis. The patient was a 27-year-old woman, without a history of gastrointestinal disease. 3 days before becoming ill, she had finished a 7-day course of ampicillin (2g/day) for bronchitis. She had colicky abdominal pain, frequent bowel movements, vomiting, and fever (40 °C), which were followed by asthenia, anorexia and mild weight loss. Abdominal signs and fever persisted for 10 days before she was admitted. On examination, the patient was moderately dehydrated and had a distended, tender abdomen. Serum-sodium was 125 mmol/l, hxmoglobin was 9 g/dl, and serum-albumin was 2.2 g/dl. Proctosigmoidoscopy showed numerous yellow-white plaques with intervening normal mucosa. Biopsy confirmed the diagnosis of pseudomembranous colitis. Barium enema showed that the whole colonic wall had a thumb-print pattern. Qualitative stool culture revealed Clostridium perfringens, Cl. butyricum, Bacteroides species, and normal aerobic flora. The patient’s general condition improved after 5 days water-electrolyte replacement and low-residue diet, but diarrhoea persisted with 8-10 liquid, malodorous stools per day. After metronidazole (1-3 g/day) was given, this improved to 3,2, and 1 soft stools/day after 24 h, 48 h, and 72 h treatment, respectively. Proctosigmoidoscopy done 7 days later showed a normal mucosa, confirmed by biopsy, and a second barium enema showed a normal mucosal pattern with only light residual motor disturbances. Metronidazole was 10. Bartlett, J. G., Change, T. W., Gurwith, M., Gorbach, S. L., Onderdonk, A. B. New Engl. J. Med. (in the press). 11. Bartlett, J. G., Onderdonk, A. B., Cisneros, R. L., Kasper, D. L. J. infect. Dis. 1977, 136, 701. 1. Rifkin, G. D., Fekety, F. R., Silva, J., Sack, R. B. Lancet, 1977, ii, 1103.
2. ibid. p. 1113.
