702
CHLORAMPHENICOL RESISTANCE IN HÆMOPHILUS INFLUENZÆ
SiR,-Ampicillin-resistant strains of H aemophilus influenza detected in at least a dozen patients in the Netherlands during 1975. The strains varied in serotype but produced a &bgr;-Iactamase. Their susceptibilities in vitro to other antibiotics were usually within normal ranges. We have lately found a strain of H. influenzae which was resistant to both chloramphenicol and tetracycline, though sensitive to ampicillin. The strain was isolated in a hospital from the pharynx of a 4-year-old girl with lymphatic leukwmia. During episodes of fever the child had been treated with short courses of ampicillin. According to the paediatrician (Dr J. C. W. Bakker) neither chloramphenicol nor tetracycline had been prescribed. Typing of the culture in one of the reference departments at this institute confirmed our provisional diagnosis of H. influenza. The strain did not belong to any known serotype (Dr J. Borst). Using dilutions in nutrient agar supplemented with X and V factor we found the strain to have minimum inhibitory concentrations of 16 g/ml for chloramphenicol and 32 p.g/ml for tetracycline; these are, respectively, about 32 and 64 times more resistant than strains of H. influence of normal sensitivity. The resistance to chloramphenicol was due to the production of an enzyme, presumably acetyltransferase. Agar supplemented with 4 g/ml of chloramphenicol was seeded with a strain of Staphylocoeeus aureus susceptible to 1-2 p.g/ml of this antibiotic. Cups were made in the agar and filled with 0-11 ml of supernatant of overnight cultures of H. influenzce in fluid medium (broth) enriched with X and V factor. One of the were
cups contained the supernatant of the resistant strain grown in the presence of 0-5g/ml of chloramphenicol, another that
of the resistant strain grown in the absence of chloramphenicol, and the third the supernatant of a strain of H. influenza, of normal sensitivity (control). The plate was then incubated (see figure). Round the cups containing the supernatants of the resistant strain growth of Staph. aureus is seen, indicating that the local concentration of chloramphenicol had diminished, probably due to an enzymic degradation of the antibiotic. Since both zones of growth were similar in size, the enzyme inactivating chloramphenicol had not been produced by induction. The experiment was repeated with 10 p.g/ml of thiamphenicol, and, as anticipated, similar results were obtained. We conclude that there is cross-resistance between these antibio-
Experiments to investigate whether the resistance is plasmid-mediated are in progress. The findings of H. influenza resistant to both chloramphenicol and tetracycline is worrying. Until now drug resistance in H. influenze has been largely confined to ampicillin. In sepsis, meningitis, or epiglottitis caused by ampicillin-resistant Hcemophilus chloramphenicol may be life-saving, and in infections of the respiratory tract the tetracyclines are reliable drugs. Any restriction of the applicability of chloramphenicol and tetracycline in Haemophilus infections may therefore present a serious problem. Our findings illustrate the need for sensitivity tests whenever this organism is isolated. tics.
National Institute of Public Health, Postbox 1, Bilthoven, Netherlands
A. MANTEN B. VAN KLINGEREN M. DESSENS-KROON
TREATMENT OF BRONCHIAL CARCINOMA
SIR,-In defending themselves against the criticism of Dr (Jan. 10, p. 84) Dr Laing and his colleagues (Feb. 21,
Stanford
428) explain that their choice of combination chemotherapy was made in 1969, but they admit that if they were choosing a combination now it would be very different. Progress in cancer chemotherapy is rapid, as witness the improved prognosis in acute leukaemias, lymphomas, choriocarcinoma, and myeloma. With new cytotoxic agents of variable p.
for their trial
potency for different types of malignancy becoming available at the rate of two or three each year the number of potential combinations, dosages and methods of administration must now be enormous.I It was Gehan and Freireich2who cast the first stone at the sacred cow of the prospective, randomised trial-if I may be permitted to indulge a weakness for mixing cliches-and the strength of their case is borne out by the 5 years which it took Laing et al. to prove that the M.v.p.p. regimen is ineffective in bronchial carcinoma. Most of the progress in medicine can be attributed to intelligent modification of previously accepted treatment by experienced clinicians, with occasional giant strides by the Fleming method of pure chance. The randomised, prospective trial is admirably suited to deciding between two new bronchodilators which differ only marginally in their effects, but there must be a better way when it comes to the chemotherapy of lung cancer.
Unfortunately the alternative approach cannot be dignified by any name other than "following your own hunch",3 which is anathema to all good scientists. The clinician who puts science second might argue that this is better than committing your dying patients of 1978 to a rigid protocol of treatment, chosen in 1976, which will by then be acknowledged as useless. Bromley Hospital Masons Hill, Bromley BR2
9JL
Chest
Clinic,
E. W. STREET
AMANTADINE AND INFLUENZA
SIR,-Epidemic influenza is spread through coughing by patients and convalescents. The experience of several generations tells us that taking aspirin or other antipyretics cannot prevent a person catching influenza, nor shorten the illness, nor reduce the duration of his infectivity. Indeed, a determined patient taking antipyretics can often remain active, spreading infection for longer than if safely in bed. drug could be taken by healthy contacts from the early of stages a local epidemic, which could keep them free of major symptoms even if they were to become infected, they might end more
If
Inactivation of chloramphenicol by resistant strain of H. influenzae.
Growth of the indicator organism sence of an exoenzyme (see text).
(Staph. aureus)
shows the pre-
a
Lloyd, H. H. Cancer Chemother, Rep. 1974, 4, 157. Gehan, E.A., Freireich, E. J. New Engl. J. Med. 1974, 290, 198. 3. Street, E. W. Proc. 9th int. Congr. Chemother. 1976, 8, 375. 1
2.
CHLORAMPHENICOL RESISTANCE IN HÆMOPHILUS INFLUENZÆ
SiR,-Ampicillin-resistant strains of H aemophilus influenza detected in at least a dozen patients in the Netherlands during 1975. The strains varied in serotype but produced a &bgr;-Iactamase. Their susceptibilities in vitro to other antibiotics were usually within normal ranges. We have lately found a strain of H. influenzae which was resistant to both chloramphenicol and tetracycline, though sensitive to ampicillin. The strain was isolated in a hospital from the pharynx of a 4-year-old girl with lymphatic leukwmia. During episodes of fever the child had been treated with short courses of ampicillin. According to the paediatrician (Dr J. C. W. Bakker) neither chloramphenicol nor tetracycline had been prescribed. Typing of the culture in one of the reference departments at this institute confirmed our provisional diagnosis of H. influenza. The strain did not belong to any known serotype (Dr J. Borst). Using dilutions in nutrient agar supplemented with X and V factor we found the strain to have minimum inhibitory concentrations of 16 g/ml for chloramphenicol and 32 p.g/ml for tetracycline; these are, respectively, about 32 and 64 times more resistant than strains of H. influence of normal sensitivity. The resistance to chloramphenicol was due to the production of an enzyme, presumably acetyltransferase. Agar supplemented with 4 g/ml of chloramphenicol was seeded with a strain of Staphylocoeeus aureus susceptible to 1-2 p.g/ml of this antibiotic. Cups were made in the agar and filled with 0-11 ml of supernatant of overnight cultures of H. influenzce in fluid medium (broth) enriched with X and V factor. One of the were
cups contained the supernatant of the resistant strain grown in the presence of 0-5g/ml of chloramphenicol, another that
of the resistant strain grown in the absence of chloramphenicol, and the third the supernatant of a strain of H. influenza, of normal sensitivity (control). The plate was then incubated (see figure). Round the cups containing the supernatants of the resistant strain growth of Staph. aureus is seen, indicating that the local concentration of chloramphenicol had diminished, probably due to an enzymic degradation of the antibiotic. Since both zones of growth were similar in size, the enzyme inactivating chloramphenicol had not been produced by induction. The experiment was repeated with 10 p.g/ml of thiamphenicol, and, as anticipated, similar results were obtained. We conclude that there is cross-resistance between these antibio-
Experiments to investigate whether the resistance is plasmid-mediated are in progress. The findings of H. influenza resistant to both chloramphenicol and tetracycline is worrying. Until now drug resistance in H. influenze has been largely confined to ampicillin. In sepsis, meningitis, or epiglottitis caused by ampicillin-resistant Hcemophilus chloramphenicol may be life-saving, and in infections of the respiratory tract the tetracyclines are reliable drugs. Any restriction of the applicability of chloramphenicol and tetracycline in Haemophilus infections may therefore present a serious problem. Our findings illustrate the need for sensitivity tests whenever this organism is isolated. tics.
National Institute of Public Health, Postbox 1, Bilthoven, Netherlands
A. MANTEN B. VAN KLINGEREN M. DESSENS-KROON
TREATMENT OF BRONCHIAL CARCINOMA
SIR,-In defending themselves against the criticism of Dr (Jan. 10, p. 84) Dr Laing and his colleagues (Feb. 21,
Stanford
428) explain that their choice of combination chemotherapy was made in 1969, but they admit that if they were choosing a combination now it would be very different. Progress in cancer chemotherapy is rapid, as witness the improved prognosis in acute leukaemias, lymphomas, choriocarcinoma, and myeloma. With new cytotoxic agents of variable p.
for their trial
potency for different types of malignancy becoming available at the rate of two or three each year the number of potential combinations, dosages and methods of administration must now be enormous.I It was Gehan and Freireich2who cast the first stone at the sacred cow of the prospective, randomised trial-if I may be permitted to indulge a weakness for mixing cliches-and the strength of their case is borne out by the 5 years which it took Laing et al. to prove that the M.v.p.p. regimen is ineffective in bronchial carcinoma. Most of the progress in medicine can be attributed to intelligent modification of previously accepted treatment by experienced clinicians, with occasional giant strides by the Fleming method of pure chance. The randomised, prospective trial is admirably suited to deciding between two new bronchodilators which differ only marginally in their effects, but there must be a better way when it comes to the chemotherapy of lung cancer.
Unfortunately the alternative approach cannot be dignified by any name other than "following your own hunch",3 which is anathema to all good scientists. The clinician who puts science second might argue that this is better than committing your dying patients of 1978 to a rigid protocol of treatment, chosen in 1976, which will by then be acknowledged as useless. Bromley Hospital Masons Hill, Bromley BR2
9JL
Chest
Clinic,
E. W. STREET
AMANTADINE AND INFLUENZA
SIR,-Epidemic influenza is spread through coughing by patients and convalescents. The experience of several generations tells us that taking aspirin or other antipyretics cannot prevent a person catching influenza, nor shorten the illness, nor reduce the duration of his infectivity. Indeed, a determined patient taking antipyretics can often remain active, spreading infection for longer than if safely in bed. drug could be taken by healthy contacts from the early of stages a local epidemic, which could keep them free of major symptoms even if they were to become infected, they might end more
If
Inactivation of chloramphenicol by resistant strain of H. influenzae.
Growth of the indicator organism sence of an exoenzyme (see text).
(Staph. aureus)
shows the pre-
a
Lloyd, H. H. Cancer Chemother, Rep. 1974, 4, 157. Gehan, E.A., Freireich, E. J. New Engl. J. Med. 1974, 290, 198. 3. Street, E. W. Proc. 9th int. Congr. Chemother. 1976, 8, 375. 1
2.
