Ampicillin-resistant strains of Hemophulus influenzae STATEMENT BY THE INFECTIOUS DISEASE AND IMMUNIZATION COMMITTEE* OF ThE CANADIAN PAEDIATRIC SOCIETY
Until recently, Hemophilus influenzae was considered reliably sensitive to ampicillin, but during 1973 and 1974 penicillinase-producing strains, resistant to ampicillin, were isolated in North America, Great Britain and Europe.1-7 At The Hospital for Sick Children in Toronto, for example, during 1974, 3 of 39 H. influenzae isolates from patients with meningitis were penicillinase-producing and ampicillin-resistant; all the resistant strains from meningitis cases were Pittman type b, but resistant untypable strains have been isolated from middle ear and posterior pharyngeal aspirates.8'9 In some, but not all, instances, meningitis or other serious infection caused by one of these strains has failed to respond to ampicillin therapy in high dosage (400 mg/kg ed).1'9 (This should not be construed to suggest that this dosage of ampicillin is safe therapy for patients with resistant strains of H. in/luenzae.) Standardizing the sensitivity test procedures for H. influenzae so that reliable and consistent results can be quickly obtained by most laboratories is difficult.t This is because of the special growth requirements of the organism and because the resistance is due to penicillinase production, which makes careful control of the amount of the inoculum critical. Unless performed expertly, disc agar diffusion methods frequently produce false results - usually false-resistance. Recommendations
The emergence of ampicillin-resistant strains has important therapeutic implications. The following regimens are recommended for the treatment of childhood bacterial meningitis; insufficient data preclude consideration of other potentially life-threatening infections caused by ampicillin-resistant strains of H. influenzae. The recommendations are based on current data and experience and are subject to change as new information becomes available. They are not designed to cover every possible clinical situation, such as complex cases of "partially treated" meningitis, and are guidelines 8Drs. R.P.B. Larke (chairman), L. Chicoine, P. D6ry, S.E. Johnson, V. Marchessault, A. Marcoux, MI. Marks, 0. Martineau, PJ. Middleton, J.D. Murray, R.L. Ozere, H. Pabst, A.R. Ronald and M.C. Smith. Reprint requests to: Canadian Paediatric Society, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Qu6. JlH 5N4
only; each case must be evaluated critically and repeatedly, and decisions may be influenced to some extent by whether ampicillin-resistant strains of H. intluenzae have been reported in the community. Two sets of recommendations are provided: the first set is for general use and most physicians should follow this alternative; the second set is for use in special institutions with a great deal of experience in treating patients with meningitis. For most cases As initial therapy, both ampicillin (400 mg/kgd divided q4h) and chioramphenicol succinate (100 mg/kg .d divided qJ2h, to a maximum of 4 g/d12) should be administered intravenously while the cause of the meningitis is being sought by microscopic examination of the smear and bacteriologic culture of the cerebrospinal fluid. The first dose of ampicillin should be started 30 minutes before the first dose of chloramphenicol, and each antibiotic should be administered within a period of 30 minutes. * If the meningitis is due to pneumococci or meningococci the chloramphenicol should be discontinued. * If the meningitis is due to H. influenzae, therapy should be continued with chloramphenicol alone (at the same dosage) if the strain is resistant to ampicillin, or with ampicillin alone (at the same dosage) if the strain is sensitive to ampicillin. For special circumstances If the physician elects to treat with ampicillin alone from the start, the following recommendations are made: * The patient should be in a unit where the medical and nursing staff are highly experienced in the management of meningitis and the child's progress can be monitored closely. * Good facilities should exist for rapid, reliable antibiotic sensitivity testing. * If the meningitis is due to H. influenzae, lumbar puncture should be tA direct test of an isolate for penicillinase (13-lactamase) production may be more practical than standard sensitivity tests.5 At The Hospital for Sick Children an adaptation of the method of Perret1O has proved practical, giving reliable results within an hour of isolation.8 A similar technique has been reported independently by Catlin.11 Details of the jodometric method and another technique currently in use to detect ampicillin-resistant strains of H. mnhluenzae at The Hospital for Sick Children will be sent to interested laboratory directors upon request to Dr. P.C. Fleming, bacteriologist in chief.
222 CMA JOURNAL/AUGUST 9, 1975/VOL. 113
repeated on the 2nd and 3rd hospital days unless it has been established by then that the strain is sensitive to ampicillin. Smears and cultures of these specimens should be examined to detect persistence of the organism. 0 Exceptions: When the child is a.lmitted unconscious or critically ill, or when ampicillin has been given for any reason shortly before admissjon, it is probably wiser to give chloramphenicol and ampicillin concomitantly, as outlined above. Notes Ampicillin rather than penicillin is recommended in combination with chloramphenicol partly because on rare occasions a strain of H. in/luenzae is resistant to chloramphenicol.13 Pneumococcal and meningococcal meningitides respond as well to ampicillin as to penicillin in the dosages recommended above. If a bactericidal (ampicillin) and a bacteriostatic (chloramphenicol) antibiotic are used concomitantly antagonism is possible,14 but if the ampicillin is given before the chloramphenicol the effect is not likely to be clinically manifest. (Experience at The Hospital for Sick Children is in accord with this conclusion.9) Chloramphenicol alone is effective in treating Hemophilus and meningococcal meningitis but there are, as yet, insufficient data to recommend it as the sole continuing therapeutic agent in cases of pneumococcal meningitis. For children with pneumococcal meningitis who are allergic to penicillin, cephaloridine is recommended.. The expert assistance of Dr. Peter C. Fleming, bacteriologist in chief at The Hospital for Sick Children, Toronto in the preparation of this statement is gratefully acknowledged. References 1. NELSON JD: Should ampicillin be abandoned for treatment of Haemophilus injluenzae disease? (E). JAMA 229: 322 1974 2. Committee on Infectious 'Diseases, American Academy of Pediatrics: Ampicillin-resistant strains of Hemophilus inlluenzae type b. Pediatrics 55: 145, 1975 3. KArz SL: Ampicillin-resistant Hemophilus inhluenzae type b: a status report. Ibid, p 6 4. TOMEN MO, STAsut SE, MCGOWAN JE ji, et al: Ampiciuin-resistant Haemophilus In! luenzae type B infection. JAMA 229: 295, 1974 5. WILLIAMS JD, KATrAN 5, CAVANAGH P: Penicillinase production by Haemophilus Influenzae. Lancet 2: 103, 1974
continued on page 227
The question has been asked whether IUDs will eventually replace oral contraceptives. If IUDs are used faithfully the pregnancy rate is less than with oral contraceptives. The greatest cause of contraceptive failure in our society is lack of sustained motivation, and for this reason IUDs are statistically more effective than pills. K.M. CROCKER, MD
Department of obstetrics and gynecology University of Saskatchewan Saskatoon, Sask.
References 1. NEWTON J, ELIAS J, MCEWAN 3, Ct al: Intrauterine contraception with the copper-7: evaluation after two years. Br Med .1 3: 447, 1974 2. TATUM HJ: The first year of clinical, experience with copper-T intra-uterine contraceptive system in the U.S. and Canada. Contraception 6: 179, 1972
Background reading 1. FoRTIER L: Obstetrics and gynecology. Audio Digest Newsletter 21: Apr 9, 1974
Prevention of Rh immunization
It is a little more than 30 years since Levine demonstrated that erythroblastosis fetalis was due to destruction of Rh-positive (D-positive) fetal erythrocytes by maternal anti-Rh (anti-D) antibodies entering the fetal circulation. Since then, there has been a remarkably rapid development of techniques for the diagnosis, treatment and prevention of this disease. We aide now on the threshold of completely eradicating the disease. It has been amply demonstrated throughout the world that the administration of anti-D-containing gamma globulin (in Canada, "Rh im-
mune globulin") to an Rh-negative mother post partum will prevent the immunization caused by her Rh-positive fetus. Prevention of failure of immunization 1. Be certain that all women requiring protection actually receive it (protective dose of anti-D, 300 p.g). 2. Protect all Rh-negative women after an abortion (recommended protective dose of anti-D, 100 pg). 3. Protect all Rh-negative women after amniocentesis (protective dose of anti-D, 100 pg). 4. In women with a massive transplacental hemorrhage a fetal bleed into the mother of more than 30 ml [incidence, 1 in every 200 pregnancies]) the standard dose of Rh immune globulin is inadequate and a larger dose must be given. Accordingly, all Rh-negative women should be tested post partum (and especially after a stillbirth) for massive transplacental hemorrhage. Such women should receive larger doses of Rh immune globulin; the dose of anti-D is based on the amount of fetal blood in the maternal circulation (i.e., 10 ..tg/ml of fetal blood). It appears that approximately 1 to 2% of Rh-negative women will be immunized despite adequate anti-D gamma globulin post partum. It is now considered that these "failures" represent women who have become immunized before delivery. For them, postpartum protection is too late. Studies are now being conducted in several parts of the world in which anti-D
gamma globulin is given at the 28th week of gestation to prevent antepartum immunization and to complete thereby the total eradication of Rh disease. Since these experimental trials are under way now and no definite results are yet available, no recommendations can be made concerning the need for prevention during pregnancy. A. ZIPURSKY, MD Department of pediatrics McMaster University Hamilton, Ont.
AMPJCILLIN-RESISTANT STRAINS continued from page 222 6. KHAN W, Ross 5, RODRIGUEZ W, et al: Haemophilus influenzae type B resistant to ampicillin. A report of two cases. JAMA 229: 298, 1974 7. GUNN BA, WOODALL JB, JONES JF: Ampicil-
un-resistant Haemophilus Lancet 2: 845, 1974
injluenzae
(C).
8. FLEMING PC, MARKOWSKY B: Recent emergence of ampicillin-resistant strains of H. injluenzae type B and their rapid detection by an jodometric method (abstr). Can J
Public Health 66: 40, 1975
9. FLEMING PC: Personal communication, November 1974 10. PERRET CJ: Todometric assay of penicilinase. Nature (Lond) 174: 1012, 1954
11. CATLIN BW: Jodometric detection of Haemo-
philus injluenzae beta-lactamase: rapid presumptive test for ampicillin-resistance. Anti-
microb Agents Chemother 7: 265, 1975 12. The Medical Letter on Drugs and Therapeutics: Handbook of Antimicrobial Therapy, revised ed, 1974, pp 22-23 13. BARRETr FF, TABER LH, Mosius CR, et al: A 12-year review of the antibiotic manage-
ment of Hemophilus tnjluenzae meningitis.
Comparison of ampicillin and conventional therapy including chioramphenicol. .F Pedlair
81: 370, 1972 14. KLEIN JO: Current usage of antimicrobial combinations in pediatrics. Pediatr Clin North Am 21: 443, 1974 15. Muasi. JD, FLEMING P, WEBER J, et al: The continuing problem of purulent meningitis in infants and children. Ibid, p 967
CMA JOURNAL/AUGUST 9, 1975/VOL. 113 227
Until recently, Hemophilus influenzae was considered reliably sensitive to ampicillin, but during 1973 and 1974 penicillinase-producing strains, resistant to ampicillin, were isolated in North America, Great Britain and Europe.1-7 At The Hospital for Sick Children in Toronto, for example, during 1974, 3 of 39 H. influenzae isolates from patients with meningitis were penicillinase-producing and ampicillin-resistant; all the resistant strains from meningitis cases were Pittman type b, but resistant untypable strains have been isolated from middle ear and posterior pharyngeal aspirates.8'9 In some, but not all, instances, meningitis or other serious infection caused by one of these strains has failed to respond to ampicillin therapy in high dosage (400 mg/kg ed).1'9 (This should not be construed to suggest that this dosage of ampicillin is safe therapy for patients with resistant strains of H. in/luenzae.) Standardizing the sensitivity test procedures for H. influenzae so that reliable and consistent results can be quickly obtained by most laboratories is difficult.t This is because of the special growth requirements of the organism and because the resistance is due to penicillinase production, which makes careful control of the amount of the inoculum critical. Unless performed expertly, disc agar diffusion methods frequently produce false results - usually false-resistance. Recommendations
The emergence of ampicillin-resistant strains has important therapeutic implications. The following regimens are recommended for the treatment of childhood bacterial meningitis; insufficient data preclude consideration of other potentially life-threatening infections caused by ampicillin-resistant strains of H. influenzae. The recommendations are based on current data and experience and are subject to change as new information becomes available. They are not designed to cover every possible clinical situation, such as complex cases of "partially treated" meningitis, and are guidelines 8Drs. R.P.B. Larke (chairman), L. Chicoine, P. D6ry, S.E. Johnson, V. Marchessault, A. Marcoux, MI. Marks, 0. Martineau, PJ. Middleton, J.D. Murray, R.L. Ozere, H. Pabst, A.R. Ronald and M.C. Smith. Reprint requests to: Canadian Paediatric Society, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Qu6. JlH 5N4
only; each case must be evaluated critically and repeatedly, and decisions may be influenced to some extent by whether ampicillin-resistant strains of H. intluenzae have been reported in the community. Two sets of recommendations are provided: the first set is for general use and most physicians should follow this alternative; the second set is for use in special institutions with a great deal of experience in treating patients with meningitis. For most cases As initial therapy, both ampicillin (400 mg/kgd divided q4h) and chioramphenicol succinate (100 mg/kg .d divided qJ2h, to a maximum of 4 g/d12) should be administered intravenously while the cause of the meningitis is being sought by microscopic examination of the smear and bacteriologic culture of the cerebrospinal fluid. The first dose of ampicillin should be started 30 minutes before the first dose of chloramphenicol, and each antibiotic should be administered within a period of 30 minutes. * If the meningitis is due to pneumococci or meningococci the chloramphenicol should be discontinued. * If the meningitis is due to H. influenzae, therapy should be continued with chloramphenicol alone (at the same dosage) if the strain is resistant to ampicillin, or with ampicillin alone (at the same dosage) if the strain is sensitive to ampicillin. For special circumstances If the physician elects to treat with ampicillin alone from the start, the following recommendations are made: * The patient should be in a unit where the medical and nursing staff are highly experienced in the management of meningitis and the child's progress can be monitored closely. * Good facilities should exist for rapid, reliable antibiotic sensitivity testing. * If the meningitis is due to H. influenzae, lumbar puncture should be tA direct test of an isolate for penicillinase (13-lactamase) production may be more practical than standard sensitivity tests.5 At The Hospital for Sick Children an adaptation of the method of Perret1O has proved practical, giving reliable results within an hour of isolation.8 A similar technique has been reported independently by Catlin.11 Details of the jodometric method and another technique currently in use to detect ampicillin-resistant strains of H. mnhluenzae at The Hospital for Sick Children will be sent to interested laboratory directors upon request to Dr. P.C. Fleming, bacteriologist in chief.
222 CMA JOURNAL/AUGUST 9, 1975/VOL. 113
repeated on the 2nd and 3rd hospital days unless it has been established by then that the strain is sensitive to ampicillin. Smears and cultures of these specimens should be examined to detect persistence of the organism. 0 Exceptions: When the child is a.lmitted unconscious or critically ill, or when ampicillin has been given for any reason shortly before admissjon, it is probably wiser to give chloramphenicol and ampicillin concomitantly, as outlined above. Notes Ampicillin rather than penicillin is recommended in combination with chloramphenicol partly because on rare occasions a strain of H. in/luenzae is resistant to chloramphenicol.13 Pneumococcal and meningococcal meningitides respond as well to ampicillin as to penicillin in the dosages recommended above. If a bactericidal (ampicillin) and a bacteriostatic (chloramphenicol) antibiotic are used concomitantly antagonism is possible,14 but if the ampicillin is given before the chloramphenicol the effect is not likely to be clinically manifest. (Experience at The Hospital for Sick Children is in accord with this conclusion.9) Chloramphenicol alone is effective in treating Hemophilus and meningococcal meningitis but there are, as yet, insufficient data to recommend it as the sole continuing therapeutic agent in cases of pneumococcal meningitis. For children with pneumococcal meningitis who are allergic to penicillin, cephaloridine is recommended.. The expert assistance of Dr. Peter C. Fleming, bacteriologist in chief at The Hospital for Sick Children, Toronto in the preparation of this statement is gratefully acknowledged. References 1. NELSON JD: Should ampicillin be abandoned for treatment of Haemophilus injluenzae disease? (E). JAMA 229: 322 1974 2. Committee on Infectious 'Diseases, American Academy of Pediatrics: Ampicillin-resistant strains of Hemophilus inlluenzae type b. Pediatrics 55: 145, 1975 3. KArz SL: Ampicillin-resistant Hemophilus inhluenzae type b: a status report. Ibid, p 6 4. TOMEN MO, STAsut SE, MCGOWAN JE ji, et al: Ampiciuin-resistant Haemophilus In! luenzae type B infection. JAMA 229: 295, 1974 5. WILLIAMS JD, KATrAN 5, CAVANAGH P: Penicillinase production by Haemophilus Influenzae. Lancet 2: 103, 1974
continued on page 227
The question has been asked whether IUDs will eventually replace oral contraceptives. If IUDs are used faithfully the pregnancy rate is less than with oral contraceptives. The greatest cause of contraceptive failure in our society is lack of sustained motivation, and for this reason IUDs are statistically more effective than pills. K.M. CROCKER, MD
Department of obstetrics and gynecology University of Saskatchewan Saskatoon, Sask.
References 1. NEWTON J, ELIAS J, MCEWAN 3, Ct al: Intrauterine contraception with the copper-7: evaluation after two years. Br Med .1 3: 447, 1974 2. TATUM HJ: The first year of clinical, experience with copper-T intra-uterine contraceptive system in the U.S. and Canada. Contraception 6: 179, 1972
Background reading 1. FoRTIER L: Obstetrics and gynecology. Audio Digest Newsletter 21: Apr 9, 1974
Prevention of Rh immunization
It is a little more than 30 years since Levine demonstrated that erythroblastosis fetalis was due to destruction of Rh-positive (D-positive) fetal erythrocytes by maternal anti-Rh (anti-D) antibodies entering the fetal circulation. Since then, there has been a remarkably rapid development of techniques for the diagnosis, treatment and prevention of this disease. We aide now on the threshold of completely eradicating the disease. It has been amply demonstrated throughout the world that the administration of anti-D-containing gamma globulin (in Canada, "Rh im-
mune globulin") to an Rh-negative mother post partum will prevent the immunization caused by her Rh-positive fetus. Prevention of failure of immunization 1. Be certain that all women requiring protection actually receive it (protective dose of anti-D, 300 p.g). 2. Protect all Rh-negative women after an abortion (recommended protective dose of anti-D, 100 pg). 3. Protect all Rh-negative women after amniocentesis (protective dose of anti-D, 100 pg). 4. In women with a massive transplacental hemorrhage a fetal bleed into the mother of more than 30 ml [incidence, 1 in every 200 pregnancies]) the standard dose of Rh immune globulin is inadequate and a larger dose must be given. Accordingly, all Rh-negative women should be tested post partum (and especially after a stillbirth) for massive transplacental hemorrhage. Such women should receive larger doses of Rh immune globulin; the dose of anti-D is based on the amount of fetal blood in the maternal circulation (i.e., 10 ..tg/ml of fetal blood). It appears that approximately 1 to 2% of Rh-negative women will be immunized despite adequate anti-D gamma globulin post partum. It is now considered that these "failures" represent women who have become immunized before delivery. For them, postpartum protection is too late. Studies are now being conducted in several parts of the world in which anti-D
gamma globulin is given at the 28th week of gestation to prevent antepartum immunization and to complete thereby the total eradication of Rh disease. Since these experimental trials are under way now and no definite results are yet available, no recommendations can be made concerning the need for prevention during pregnancy. A. ZIPURSKY, MD Department of pediatrics McMaster University Hamilton, Ont.
AMPJCILLIN-RESISTANT STRAINS continued from page 222 6. KHAN W, Ross 5, RODRIGUEZ W, et al: Haemophilus influenzae type B resistant to ampicillin. A report of two cases. JAMA 229: 298, 1974 7. GUNN BA, WOODALL JB, JONES JF: Ampicil-
un-resistant Haemophilus Lancet 2: 845, 1974
injluenzae
(C).
8. FLEMING PC, MARKOWSKY B: Recent emergence of ampicillin-resistant strains of H. injluenzae type B and their rapid detection by an jodometric method (abstr). Can J
Public Health 66: 40, 1975
9. FLEMING PC: Personal communication, November 1974 10. PERRET CJ: Todometric assay of penicilinase. Nature (Lond) 174: 1012, 1954
11. CATLIN BW: Jodometric detection of Haemo-
philus injluenzae beta-lactamase: rapid presumptive test for ampicillin-resistance. Anti-
microb Agents Chemother 7: 265, 1975 12. The Medical Letter on Drugs and Therapeutics: Handbook of Antimicrobial Therapy, revised ed, 1974, pp 22-23 13. BARRETr FF, TABER LH, Mosius CR, et al: A 12-year review of the antibiotic manage-
ment of Hemophilus tnjluenzae meningitis.
Comparison of ampicillin and conventional therapy including chioramphenicol. .F Pedlair
81: 370, 1972 14. KLEIN JO: Current usage of antimicrobial combinations in pediatrics. Pediatr Clin North Am 21: 443, 1974 15. Muasi. JD, FLEMING P, WEBER J, et al: The continuing problem of purulent meningitis in infants and children. Ibid, p 967
CMA JOURNAL/AUGUST 9, 1975/VOL. 113 227
