1462
be ascertained since the parents removed the child after there no improvement within 48 hours of treatment with pivmecillinam. Patient 5 showed a delayed response to pivmecillinam. Patients 2 and 3 improved on ciprofloxacin, a 4-quinolone drug and patient 4 on ceftriazone, a third-generation
not
was
PERCENTAGE OF SEROCONVERTERS AND ANTIBODY TITRES AFTER RABIES POSTEXPOSURE VACCINATION WITH 2-2 AND 2-1-1 SCHEDULES
cephalosporin. The few resistant species indentified were exclusively confined to dysenteriae type 1, which is known to cause severe illness. Although resistance to pivmecillinam was not very high, its pattern should be carefully monitored. The lower resistance to pivmecillinam may be because it is not widely used in this country, partly because it is expensive (US$5 vs US$1 for nalidixic acid per child weighing 12 kg per episode), and partly because it is not readily available on the market. Secondly, pivmecillinam, in contrast to other beta-lactams, selectively binds to penicillin-binding protein; it is stable to most beta-lactamases and penetrates into the bacterial cell wall more efficiently. As a result, resistance among Enterobacteriaceae, including shigella, to pivmecillinam is less common.4 In most developing countries where antibiotics are available without a prescription, there should be public awareness against the misuse of antibiotics. At the same time, some useful but expensive drugs, such as pivmecillinam, ceftriaxone, and ciprofloxacin, should be used with caution to prevent or slow down the emergence of drug resistance, which seems inevitable with widespread and indiscriminate use.
S
Clinical Research Centre, International Centre for Diarrhoeal Disease Research B, GPO Box 128, Dhaka 1000,
Bangladesh
AMAL K. MITRA IQBAL KABIR M. ANOWAR HOSSAIN
2-2
immunity might develop promptly after 4 doses.5 This new schedule is promising and can be proposed for rabies postexposure vaccination in patients without impaired immune responsebut the results need to be confirmed with the new vaccine grown on Vero
cells.’ We thank Catherine Gilliot for technical assistance.
Service of Infectious and Tropical Diseases, Hôpital du Bocage, BP 1542, 21034 Dijon Cedex, France
1. 1. Bennish ML, Kay BA, Eusof A, Wierzba T. Multiresistant shigellosis in Bangladesh. Lancet 1985; ii: 441. 2. Munshi MH, Sack DA, Haider K, Ahmed ZU, Rahaman MM, Morshed MG. Plasmid-mediated resistance to nalidixic acid in Shigella dysenteriae type 1. Lancet 1987; ii: 419-21. 3. Kabir I, Rahaman MM, Ahmed SM, Akhter SQ, Butler T. Comparative efficacies of pivmecillinam and ampicillin in acute shigellosis. Antimicrob Agents Chemother
2.
3.
1984; 25: 643-45. 4. Kucers A, Bennett NM. The use of antibiotics: a comprehensive review with clinical emphasis. 4th ed. London: William Heinemann Medical Books, 1988: 256-61.
4.
5.
Abbreviated schedule for rabies
postexposure prophylaxis SIR,-Dr Chutivongse and colleagues (April 14, p 896) report the Thai Red Cross intradermal post-exposure rabies treatment schedule. However, the intradermal route is almost never used in France. We have shown that the "2-1-1" schedule’ is successful2 and that a one-year booster dose gives a strong antibody response.3 Since a dose response would be expected with the human diploid cell rabies vaccine (HDCV),’ and to further reduce the number of visits, and thus the cost, we randomly compared this schedule with a "2-2" schedule-2 doses at day 0 and 2 at day 7. HDCV (titrated 2-5 IU/ml) was given intramuscularly. The antibodies were measured by ELISA (EU/ml) at day 0,7,14,30, and 90. 65 adults were enrolled randomly. All subjects seroconverted, whatever the schedule used. Only 1 patient aged 66, who received 2-2, did not reach the 0-5 EU/ml antibody regarded as the threshold for protection, antibody concentrations were 0-2 and 0-3 EU/ml at day 7 and 14, respectively. At day 14, no differences were seen in the percentage of subjects who had seroconverted (above 05 EU/ml or 1 EU/ml) or in antibody titres between the two schedules. At day 30, antibody titres were higher in the 2-1-1 schedule group, but the percentage of subjects with antibody concentrations over 0-5 EU/ml did not differ between the groups. However, with respect to a threshold of 1 EU/ml, all subjects on the 2-1-1 schedule were protected versus only 83% with 2-2 (table). These differences were not linked to gender or age (data not shown). At day 90, both schedules gave similar protection but titres were higher with 2-1-1. No serious side-effects were noted. Although the dose/antibody-response hypothesis is not confirmed by this study, since the 2-2 schedule did not give higher titres at day 14, we cannot exclude the possibility that cell-mediated
2-1-1:*p=0 024 (Fisher exact test); tp < 01 (Student t test)
6.
7.
PASCAL CHAVANET CHANTAL GREBERT ANNE WALDNER HENRI PORTIER
Vodopija I, Sureau P,
Laffon M, et al. An evaluation of second generation tissue culture rabies vaccine for use in man: a four-vaccine comparative immunogenicity study using a pre-exposure vaccination schedule and an abbreviated 2-1-1 post-exposure schedule. Vaccine 1986; 4: 245-48. Chavanet P, Sureau P, Waldner-Combernoux A, et al. Schéma simplifié pour la vaccination antirabique après exposition. Presse Med 1989; 18: 813-15. Chavanet P, Buisson M, Waldner-Combernoux A, et al. Vaccination antirabique après exposition par schema simplifié 2-1-1: effet d’une dose de rappel à un an. Sem Hôp Paris 1989; 65: 2557-60. Fishbein DB, Pacer RE, Holmes DF, Ley AB, Yager P, Tong TC. Rabies preexposure prophylaxis with human diploid cell rabies vaccine: a dose-response study. J Infect Dis 1987; 156: 50-55. Nicholson KG, Cole PJ, Turner GS, Harrison P. Immune response of humans to a human diploid cell strain of rabies virus vaccine: lymphocyte transformation, production of virus-neuralizing antibody, and induction of interferon. J Infect Dis 1979; 140: 176-82. Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies post-exposure treatment in Thailand. Vaccine 1989; 7: 49-52. Ajjan N, Pilet C. Comparative study of the safety and the protective value, in pre-exposure of rabies vaccine cultivated on human diploid cells (HDCV) and the new vaccine grown on Vero cell. Vaccine 1989; 7: 125-28.
Origins of genetic disease SiR,—Your April 14 editorial draws attention to the strong bias a paternal origin for many de-novo germline mutations (excluding aneuploid). Cytological studies1 show a preferential tendency for structural rearrangements to be paternally derived, and molecular investigations give the same indications for the germinal mutations in retinoblastoma,z Prader-Willi syndrome3 and von Recklinghausen neurofibromatosis.4 Like others1,2you towards
suggest that males show
more
mutations than females because
usually arise during cell division in the proliferating spermatogonia, oocytes in the adult being arrested in the diplotene errors
stage of meiotic prophase. This hypothesis was put forward by Penrose6 to explain the strong paternal age effect associated with single-gene disorders such as achondroplasia and Marfan syndrome; but, as you point out, no obvious association with paternal age has been demonstrated for retinoblastoma or neurofibromatosis. Nor has it been found for de-novo structural rearrangements of paternal origin.1 One important factor is often overlooked. The inheritance of a mutation through the male germline will depend not only on the sensitivity to induction of a particular stage of spermatogenesis but also on the chances of detecting the cell carrying the mutation in mature sperm. Early mutagenesis workers using Drosophila found
be ascertained since the parents removed the child after there no improvement within 48 hours of treatment with pivmecillinam. Patient 5 showed a delayed response to pivmecillinam. Patients 2 and 3 improved on ciprofloxacin, a 4-quinolone drug and patient 4 on ceftriazone, a third-generation
not
was
PERCENTAGE OF SEROCONVERTERS AND ANTIBODY TITRES AFTER RABIES POSTEXPOSURE VACCINATION WITH 2-2 AND 2-1-1 SCHEDULES
cephalosporin. The few resistant species indentified were exclusively confined to dysenteriae type 1, which is known to cause severe illness. Although resistance to pivmecillinam was not very high, its pattern should be carefully monitored. The lower resistance to pivmecillinam may be because it is not widely used in this country, partly because it is expensive (US$5 vs US$1 for nalidixic acid per child weighing 12 kg per episode), and partly because it is not readily available on the market. Secondly, pivmecillinam, in contrast to other beta-lactams, selectively binds to penicillin-binding protein; it is stable to most beta-lactamases and penetrates into the bacterial cell wall more efficiently. As a result, resistance among Enterobacteriaceae, including shigella, to pivmecillinam is less common.4 In most developing countries where antibiotics are available without a prescription, there should be public awareness against the misuse of antibiotics. At the same time, some useful but expensive drugs, such as pivmecillinam, ceftriaxone, and ciprofloxacin, should be used with caution to prevent or slow down the emergence of drug resistance, which seems inevitable with widespread and indiscriminate use.
S
Clinical Research Centre, International Centre for Diarrhoeal Disease Research B, GPO Box 128, Dhaka 1000,
Bangladesh
AMAL K. MITRA IQBAL KABIR M. ANOWAR HOSSAIN
2-2
immunity might develop promptly after 4 doses.5 This new schedule is promising and can be proposed for rabies postexposure vaccination in patients without impaired immune responsebut the results need to be confirmed with the new vaccine grown on Vero
cells.’ We thank Catherine Gilliot for technical assistance.
Service of Infectious and Tropical Diseases, Hôpital du Bocage, BP 1542, 21034 Dijon Cedex, France
1. 1. Bennish ML, Kay BA, Eusof A, Wierzba T. Multiresistant shigellosis in Bangladesh. Lancet 1985; ii: 441. 2. Munshi MH, Sack DA, Haider K, Ahmed ZU, Rahaman MM, Morshed MG. Plasmid-mediated resistance to nalidixic acid in Shigella dysenteriae type 1. Lancet 1987; ii: 419-21. 3. Kabir I, Rahaman MM, Ahmed SM, Akhter SQ, Butler T. Comparative efficacies of pivmecillinam and ampicillin in acute shigellosis. Antimicrob Agents Chemother
2.
3.
1984; 25: 643-45. 4. Kucers A, Bennett NM. The use of antibiotics: a comprehensive review with clinical emphasis. 4th ed. London: William Heinemann Medical Books, 1988: 256-61.
4.
5.
Abbreviated schedule for rabies
postexposure prophylaxis SIR,-Dr Chutivongse and colleagues (April 14, p 896) report the Thai Red Cross intradermal post-exposure rabies treatment schedule. However, the intradermal route is almost never used in France. We have shown that the "2-1-1" schedule’ is successful2 and that a one-year booster dose gives a strong antibody response.3 Since a dose response would be expected with the human diploid cell rabies vaccine (HDCV),’ and to further reduce the number of visits, and thus the cost, we randomly compared this schedule with a "2-2" schedule-2 doses at day 0 and 2 at day 7. HDCV (titrated 2-5 IU/ml) was given intramuscularly. The antibodies were measured by ELISA (EU/ml) at day 0,7,14,30, and 90. 65 adults were enrolled randomly. All subjects seroconverted, whatever the schedule used. Only 1 patient aged 66, who received 2-2, did not reach the 0-5 EU/ml antibody regarded as the threshold for protection, antibody concentrations were 0-2 and 0-3 EU/ml at day 7 and 14, respectively. At day 14, no differences were seen in the percentage of subjects who had seroconverted (above 05 EU/ml or 1 EU/ml) or in antibody titres between the two schedules. At day 30, antibody titres were higher in the 2-1-1 schedule group, but the percentage of subjects with antibody concentrations over 0-5 EU/ml did not differ between the groups. However, with respect to a threshold of 1 EU/ml, all subjects on the 2-1-1 schedule were protected versus only 83% with 2-2 (table). These differences were not linked to gender or age (data not shown). At day 90, both schedules gave similar protection but titres were higher with 2-1-1. No serious side-effects were noted. Although the dose/antibody-response hypothesis is not confirmed by this study, since the 2-2 schedule did not give higher titres at day 14, we cannot exclude the possibility that cell-mediated
2-1-1:*p=0 024 (Fisher exact test); tp < 01 (Student t test)
6.
7.
PASCAL CHAVANET CHANTAL GREBERT ANNE WALDNER HENRI PORTIER
Vodopija I, Sureau P,
Laffon M, et al. An evaluation of second generation tissue culture rabies vaccine for use in man: a four-vaccine comparative immunogenicity study using a pre-exposure vaccination schedule and an abbreviated 2-1-1 post-exposure schedule. Vaccine 1986; 4: 245-48. Chavanet P, Sureau P, Waldner-Combernoux A, et al. Schéma simplifié pour la vaccination antirabique après exposition. Presse Med 1989; 18: 813-15. Chavanet P, Buisson M, Waldner-Combernoux A, et al. Vaccination antirabique après exposition par schema simplifié 2-1-1: effet d’une dose de rappel à un an. Sem Hôp Paris 1989; 65: 2557-60. Fishbein DB, Pacer RE, Holmes DF, Ley AB, Yager P, Tong TC. Rabies preexposure prophylaxis with human diploid cell rabies vaccine: a dose-response study. J Infect Dis 1987; 156: 50-55. Nicholson KG, Cole PJ, Turner GS, Harrison P. Immune response of humans to a human diploid cell strain of rabies virus vaccine: lymphocyte transformation, production of virus-neuralizing antibody, and induction of interferon. J Infect Dis 1979; 140: 176-82. Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies post-exposure treatment in Thailand. Vaccine 1989; 7: 49-52. Ajjan N, Pilet C. Comparative study of the safety and the protective value, in pre-exposure of rabies vaccine cultivated on human diploid cells (HDCV) and the new vaccine grown on Vero cell. Vaccine 1989; 7: 125-28.
Origins of genetic disease SiR,—Your April 14 editorial draws attention to the strong bias a paternal origin for many de-novo germline mutations (excluding aneuploid). Cytological studies1 show a preferential tendency for structural rearrangements to be paternally derived, and molecular investigations give the same indications for the germinal mutations in retinoblastoma,z Prader-Willi syndrome3 and von Recklinghausen neurofibromatosis.4 Like others1,2you towards
suggest that males show
more
mutations than females because
usually arise during cell division in the proliferating spermatogonia, oocytes in the adult being arrested in the diplotene errors
stage of meiotic prophase. This hypothesis was put forward by Penrose6 to explain the strong paternal age effect associated with single-gene disorders such as achondroplasia and Marfan syndrome; but, as you point out, no obvious association with paternal age has been demonstrated for retinoblastoma or neurofibromatosis. Nor has it been found for de-novo structural rearrangements of paternal origin.1 One important factor is often overlooked. The inheritance of a mutation through the male germline will depend not only on the sensitivity to induction of a particular stage of spermatogenesis but also on the chances of detecting the cell carrying the mutation in mature sperm. Early mutagenesis workers using Drosophila found
