1183 is
Letters
to
the Editor
ANTIBIOTIC PROPHYLAXIS FOR PATIENTS IN PROTECTIVE ISOLATION
no
evidence that oral
against graft-versus-host
cyclosporin A given as prophylaxis disease makes any difference to the
stool bacterial flora. On the grounds of patient comfort and economy the Royal Marsden Hospital leukaemia unit now suggests that the following regimen along with protective isolation gives practical decontamination for patients with acute non-lymphoblastic leukxmia: ’
SIR,-In October, 1977, you published a paper’ from the Royal Marsden, Hammersmith, and St. Mary’s Hospitals on
patients with acute non-lymphoblastic leukxmia nursed in protective isolation and given the oral non-absorbable antibiotics framycetin, colistin, and nystatin (FRACON), together with cutaneous and mucosal antiseptic preparations (mainly chlorhexidine compounds), or none of these. The patients on antibiotic prophylaxis had significantly fewer infections, fewer deaths from infection, fewer pyrexial episodes, and less systemic antibiotic therapy than did the patients who, though similarly nursed in protective isolation, did not receive this regimen. Since the beginning of 1978 the regimen originally described has been altered to halve the number of tablets taken and to reduce greatly the topical antiseptics, whilst maintaining adequate suppression of microbial flora. Oral neomycin has replaced framycetin, thereby halving the cost of each dose. The only topical antiseptic used routinely is twice daily chlorhexidine obstetric cream (1%) to the vagina and vulva. Chlorhexidine mouthwashes (0-02% aqueous) are used only if necessary.
From Jan. 1, 1978, to April 1, 1979, this new regimen has been used on 38 occasions, all patients having acute non-lymphoblastic leukaemia, newly diagnosed or in first relapse. The comparison between the previous regimen and the neomycin, colistin, nystatin (NEOCON) regimen is shown in the accompanying table. Patients intolerant of the regimen were not inCOMPARISON OF FRACON AND NEOCON REGIMENS
eluded in these studies. Despite chemotherapy policies being if anything more anti-leukæmic, it would seem that there is slightly less severe neutropenia, although the time with less is the same. The differences in fever of systemic antibiotic therapy are insignificant, and no patient has died of infection in the present series. Stools were judged satisfactory in 91% of patients studied. 3 patients had unsatisfactory stools. 1 patient’s stools were considered unsatisfactory since pseudomonas was grown on one occasion from the stool and the other two were unsatisfactory in that Escherichia coli could not be eliminated. 4 patients were excluded from the study as they could not tolerate even this reduced amount of gut antibiotics. In addition, 14 acute non-lymphoblastic leukaemic patients who tolerated the NEOCON regimen underwent marrow transplantation with cyclophosphamide and total body irradiation. These patients received the same regimen and protective isolation for 384 days during which time they had 55 (14%) days of pyrexia and 139 (36%) days of systemic antibiotics. Therc
than 500
neutrophils/µ1
days and days
R. A., Jameson, A S. D., Gaya, H. Lancet,
1. Storring,
B., McElwain, T. J., Wiltshaw, E., Spiers, 1977, ii, 837.
Neomycin sulphate 500 mg Colistin sulphate 1.5 x 106 units Nystatin 0’5xx106 units, Nystatin 0.1 x 106 units, Chlorhexidine obstetric twice daily
Amphotericin
B
Leukæmia Unit, Royal Marsden Hospital, Sutton, Surrey SM2 5PT
THE
cream
tablet twice daily one tablet twice daily one tablet twice daily as syrup twice daily (1%)) to vagina and vulva
lozenges (10 mg)
one
sucked four times
a
day
J. GRAHAM WATSON BERYL JAMESON
MALARIA/G.-6-P.D. HYPOTHESIS
SIR,-We read with great interest the paper by Dr Martin and
colleagues (March 10, p. 524) on the relation between glucose-6-phosphate dehydrogenase (G.-6-P.D.) deficiency and malaria. Their main objective seems to have been to attempt to verify our data,’ and their study design was almost identical Their results, and some of their inferences, are not in conflict with ours; all the same Martin et al. conclude that "evidence is lacking" for relative protection against malaria of females heterozygous for G.-6-P.D. deficiency. We suggest that this is due to inadequacy of their own data, not to overinterpretation by us of our Martin et al. agree with us’ that there is no protection against malaria in G.-6-P.D.-deficient hemizygous (GdA-) boys or homozygous (GdA-/GdA-) girls. The reanalysis of our data (in their table n) is not relevant to our claim that heterozygotes are protected, so we shall confine our further comments to this claim. to ours.
findings.’
Martin et al. state that our cellular studies on the preferential infection of G.-6-P.D. (+) red cells in heterozygotes2 must be re-evaluated because of "the recent observation that P. falciparum preferentially invades reticulocytes". We made the same observation in our own study and, although teaching at the time was to the contrary,3 we did point out that "in G.-6-P.D. deficient subjects, the parasites tend to invade the youngest cells. This may or may not apply to other subjects". However, we believe that not all of the difference in parasitisation between G.-6-P.D. (+) and G.-6-P.D. (-) red blood-cells is due to reticulocytosis, because reticulocytes are usually not much increased in children with malaria’ and because the percentage of G.-6-P.D. (-) red cells we have counted is in the same range as observed elsewhere in a random sample of healthy Gd+/Gd- heterozygotes.4 In heterozygotes plasmodia are confronted with approximately equal proportions of the two cell types. Perhaps this is what makes proliferation up to dangerous levels difficult for them, and it may not matter whether a particular red cell has a higher G.-6-P.D. level because it is G.-6-P.D. (+) or because it is a G.-6-P.D. (-) reticulocyte. The statement that our results2 "are not necessarily causally related to G.-6-P.D. activity" is not correct; G.-6-P.D. activity is higher in reticulocytes. Martin et al. criticise the inference we drew from our data on heterozygotes because we analysed GdB/GdA- separately from GdA/GdA-, whereas from "considerations of population genetics" we should have looked for a selective advantage of heterozygotes as a whole. In fact, the considerations briefly outlined in their paper could be more complex in three-allele rather than two-allele polymorphism. When we started our work, we knew that G.-6-P.D. was a three-allele polymorphic system in Nigeria, and we knew the frequencies of Gd, Gd, and GdA-.5 We had an open mind as to which genotype(s) might be protective, so we did our statistical analysis in the conventional way. For
1. Bienzle, U., Ayeni, O., Lucas, A. O., Luzzatto, L. Lancet, 1972, i, 107. 2. Luzzatto, L., Usanga, A. E., Reddy, S. Science, 1969, 164, 839. 3. Chwatt, L. J. Ann. trop. Med. Parasit. 1948, 42, 101. 4. Rinaldi, A., Filippi, G., Siniscalco, M. Am. J. hum. Genet. 1976, 28, 496. 5. Luzzatto, L., Allan, N. C. Nature, 1968, 219, 1041.
Letters
to
the Editor
ANTIBIOTIC PROPHYLAXIS FOR PATIENTS IN PROTECTIVE ISOLATION
no
evidence that oral
against graft-versus-host
cyclosporin A given as prophylaxis disease makes any difference to the
stool bacterial flora. On the grounds of patient comfort and economy the Royal Marsden Hospital leukaemia unit now suggests that the following regimen along with protective isolation gives practical decontamination for patients with acute non-lymphoblastic leukxmia: ’
SIR,-In October, 1977, you published a paper’ from the Royal Marsden, Hammersmith, and St. Mary’s Hospitals on
patients with acute non-lymphoblastic leukxmia nursed in protective isolation and given the oral non-absorbable antibiotics framycetin, colistin, and nystatin (FRACON), together with cutaneous and mucosal antiseptic preparations (mainly chlorhexidine compounds), or none of these. The patients on antibiotic prophylaxis had significantly fewer infections, fewer deaths from infection, fewer pyrexial episodes, and less systemic antibiotic therapy than did the patients who, though similarly nursed in protective isolation, did not receive this regimen. Since the beginning of 1978 the regimen originally described has been altered to halve the number of tablets taken and to reduce greatly the topical antiseptics, whilst maintaining adequate suppression of microbial flora. Oral neomycin has replaced framycetin, thereby halving the cost of each dose. The only topical antiseptic used routinely is twice daily chlorhexidine obstetric cream (1%) to the vagina and vulva. Chlorhexidine mouthwashes (0-02% aqueous) are used only if necessary.
From Jan. 1, 1978, to April 1, 1979, this new regimen has been used on 38 occasions, all patients having acute non-lymphoblastic leukaemia, newly diagnosed or in first relapse. The comparison between the previous regimen and the neomycin, colistin, nystatin (NEOCON) regimen is shown in the accompanying table. Patients intolerant of the regimen were not inCOMPARISON OF FRACON AND NEOCON REGIMENS
eluded in these studies. Despite chemotherapy policies being if anything more anti-leukæmic, it would seem that there is slightly less severe neutropenia, although the time with less is the same. The differences in fever of systemic antibiotic therapy are insignificant, and no patient has died of infection in the present series. Stools were judged satisfactory in 91% of patients studied. 3 patients had unsatisfactory stools. 1 patient’s stools were considered unsatisfactory since pseudomonas was grown on one occasion from the stool and the other two were unsatisfactory in that Escherichia coli could not be eliminated. 4 patients were excluded from the study as they could not tolerate even this reduced amount of gut antibiotics. In addition, 14 acute non-lymphoblastic leukaemic patients who tolerated the NEOCON regimen underwent marrow transplantation with cyclophosphamide and total body irradiation. These patients received the same regimen and protective isolation for 384 days during which time they had 55 (14%) days of pyrexia and 139 (36%) days of systemic antibiotics. Therc
than 500
neutrophils/µ1
days and days
R. A., Jameson, A S. D., Gaya, H. Lancet,
1. Storring,
B., McElwain, T. J., Wiltshaw, E., Spiers, 1977, ii, 837.
Neomycin sulphate 500 mg Colistin sulphate 1.5 x 106 units Nystatin 0’5xx106 units, Nystatin 0.1 x 106 units, Chlorhexidine obstetric twice daily
Amphotericin
B
Leukæmia Unit, Royal Marsden Hospital, Sutton, Surrey SM2 5PT
THE
cream
tablet twice daily one tablet twice daily one tablet twice daily as syrup twice daily (1%)) to vagina and vulva
lozenges (10 mg)
one
sucked four times
a
day
J. GRAHAM WATSON BERYL JAMESON
MALARIA/G.-6-P.D. HYPOTHESIS
SIR,-We read with great interest the paper by Dr Martin and
colleagues (March 10, p. 524) on the relation between glucose-6-phosphate dehydrogenase (G.-6-P.D.) deficiency and malaria. Their main objective seems to have been to attempt to verify our data,’ and their study design was almost identical Their results, and some of their inferences, are not in conflict with ours; all the same Martin et al. conclude that "evidence is lacking" for relative protection against malaria of females heterozygous for G.-6-P.D. deficiency. We suggest that this is due to inadequacy of their own data, not to overinterpretation by us of our Martin et al. agree with us’ that there is no protection against malaria in G.-6-P.D.-deficient hemizygous (GdA-) boys or homozygous (GdA-/GdA-) girls. The reanalysis of our data (in their table n) is not relevant to our claim that heterozygotes are protected, so we shall confine our further comments to this claim. to ours.
findings.’
Martin et al. state that our cellular studies on the preferential infection of G.-6-P.D. (+) red cells in heterozygotes2 must be re-evaluated because of "the recent observation that P. falciparum preferentially invades reticulocytes". We made the same observation in our own study and, although teaching at the time was to the contrary,3 we did point out that "in G.-6-P.D. deficient subjects, the parasites tend to invade the youngest cells. This may or may not apply to other subjects". However, we believe that not all of the difference in parasitisation between G.-6-P.D. (+) and G.-6-P.D. (-) red blood-cells is due to reticulocytosis, because reticulocytes are usually not much increased in children with malaria’ and because the percentage of G.-6-P.D. (-) red cells we have counted is in the same range as observed elsewhere in a random sample of healthy Gd+/Gd- heterozygotes.4 In heterozygotes plasmodia are confronted with approximately equal proportions of the two cell types. Perhaps this is what makes proliferation up to dangerous levels difficult for them, and it may not matter whether a particular red cell has a higher G.-6-P.D. level because it is G.-6-P.D. (+) or because it is a G.-6-P.D. (-) reticulocyte. The statement that our results2 "are not necessarily causally related to G.-6-P.D. activity" is not correct; G.-6-P.D. activity is higher in reticulocytes. Martin et al. criticise the inference we drew from our data on heterozygotes because we analysed GdB/GdA- separately from GdA/GdA-, whereas from "considerations of population genetics" we should have looked for a selective advantage of heterozygotes as a whole. In fact, the considerations briefly outlined in their paper could be more complex in three-allele rather than two-allele polymorphism. When we started our work, we knew that G.-6-P.D. was a three-allele polymorphic system in Nigeria, and we knew the frequencies of Gd, Gd, and GdA-.5 We had an open mind as to which genotype(s) might be protective, so we did our statistical analysis in the conventional way. For
1. Bienzle, U., Ayeni, O., Lucas, A. O., Luzzatto, L. Lancet, 1972, i, 107. 2. Luzzatto, L., Usanga, A. E., Reddy, S. Science, 1969, 164, 839. 3. Chwatt, L. J. Ann. trop. Med. Parasit. 1948, 42, 101. 4. Rinaldi, A., Filippi, G., Siniscalco, M. Am. J. hum. Genet. 1976, 28, 496. 5. Luzzatto, L., Allan, N. C. Nature, 1968, 219, 1041.
