930
and 62 survivors of myocardial infarction enrolled 3 months after the acute index event. A positive test for aPL was obtained in 3 (25%) TIA patients and in 8 (13%) myocardial infarction survivors. Blood samples for aPL measurement were obtained at least 3 months after the last ischaemic or necrotic event, so the increased aPL values in our patients were probably not due to the acute phase of tissue necrosis. During 24 months’ follow-up, three major thrombotic events (two in TIA patients and one in a myocardial infarction survivor) were seen in aPL-negative subjects, and none took place in the aPL-positive group. Our results are consistent with Sletnes and colleagues’ suggestion that aPL is not a risk factor for coronary or cerebrovascular thrombotic sequelae in patients with previous myocardial infarction or TIA.
Istituto di Medicina Interna, Milan University, 20122 Milano, Italy
MICHELE CORTELLARO CARLA BOSCHETTI MASSIMO CARDILLO TIZIANO BARBUI
The main investigators in the PLAT study are: Dr Michele Cortellaro, Dr Carlo Boschetti, Dr Elisabetta Cofrancesco, Dr Mariella Catalano, Dr Livio Gabrielli, Dr Giovanni de Gaetano, Dr Bruno Lombardi, Dr Guiseppe Specchta, Dr Luigi Tavazzi, Dr Elena Tremoli, and Dr Carlo Zanussi.
1. Hamsten A, Norberg R, Bjorkholm M, De Faire U, Holm G. Antibodies to cardiolipin m young survivors of myocardial infarction: an association with recurrent cardiovascular events. Lancet 1986; i: 113-16. 2. Cortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients. Atherosclerosis 1991; 90: 109-1 1.
Orchidopexy and transformation of seminoma to non-seminoma SIR,-Undescended testes are the only unequivocal risk factor for testicular germ-cell tumours.1 Whether surgical correction determines the histology of subsequent testicular tumours has received increasing attention.2,3 We have reviewed retrospectively patients with testes tumours who were referred to one of us (R.T.D.O.) during 1978-90. History of undescended testis, side of involvement, and operative correction, if any, was elicited by direct questioning of patients, and examination of hospital records and general practitioners’ notes. Histological findings for orchidectomy specimens or other tissues were reviewed by a second team of pathologists wherever possible. Of the 319 cases with adequate information, 119 were seminomas and 200 were malignant teratomas. 28 patients had a history of undescended testes (88%); in 7 of these, this was bilateral. 14 patients in the seminoma group and 14 in the malignant teratoma group had a positive history of undescended testes. 3 with seminoma and 10 with malignant teratoma had orchidopexy-2 and 10, respectively, on the same side as the subsequent tumour. Three-quarters of tumours in patients with uncorrected cryptorchidism were seminomas, whereas over 80% of tumours that developed after surgical correction were malignant teratomas (table). Of the patients with normally descended testes, 37% (119/319) had seminomas. No significant differences were detected between patients with stage 1 disease and those with metastatic disease, although there was a trend for more metastatic disease in patients with corrected cryptorchidism. The role of undescended testes in the pathogenesis of testicular tumours is yet to be defined. It is increasingly accepted that development of testicular cancer is a multistep process, going from carcinoma in situ through seminoma to malignant teratoma.4 Germinal epithelial atrophy has been postulated as the common pathway5 since it produces decreased feedback inhibition of the hypothalamus and increased gonadal hormonal drive, allowing less time for repair of DNA damage from environmental mutagens in the reduced number of germ cells. This hypothesis was based on the observation that many of the aetiologically associated risk factors for testicular tumours, whether intrinsic (genetic, hormonal) or extrinsic (trauma, viral infections, hormones), induced testicular atrophy. Several studies have suggested that vasectomy or operative correction of previous inguinal hernia, especially when complicated by haematoma,’* seem to increase the risk of subsequent malignant
EFFECT OF SURGICAL CORRECTION ON DEVELOPMENT OF TUMOURS IN PATIENTS WITH OR WITHOUT CRYPTORCHIDISM I
I
-
...
*p < 0 006, operated vs non-operated tall patients
disease, although the role of direct trauma remains controversial and .6 may merely draw the patient’s attention to that testis In this series, the 8-8% frequency of undescended testis is in
keeping with those of other studies. It is noteworthy that in the seminoma group with undescended testes, only 2 (15%) patients had corrective orchidopexy on the side of malignant disease, whereas in the non-seminoma group, nearly three-quarters (10 of 14) of patients with undescended testes had previous orchidopexy on that side. Other workers have also reported such findings (ref3 3 and Jones BJ et al, unpublished). These three studies suggest that operative correction of undescended testes increases the chances of subsequent malignant teratoma. Postoperative atrophy due to diminished vascular supply, with increased gonadotropin drive, could promote the transformation of seminoma to malignant teratoma. In view of the small number of cases involved, the results need to be interpreted with caution. Even if our fmdings are confirmed, it is clear that surgical correction of undescended testes should continue, in view of the psychological effects, ease of earlier diagnosis, and higher cure rate should malignant disease develop. However, perhaps more careful attention should be given at operation to vascular supply of the testes.’7 M. A. RAJA R. T. D. OLIVER D. BADENOCH Royal London Hospital, London E1 2AD, UK J. P. BLANDY C, Pike MC. Epidemiology of undescended testes. In: Oliver RTD, Blandy JP, Hope-Stone HF, eds. Oxford: Blackwell Scientific, 1989: 306-21. Pike MC, Chilvers C, Peckham MJ. Effect of age at orchidopexy on risk of testicular
1. Chilvers
2.
cancer. Lancet 1986; i 1246-48. 3. Halme A, Kellokumpu-Lehtinen P, Lehtonen T, Teppo L. Morphology of testicular germ cell tumours in treated and untreated cryptorchidism. Br J Urol 1989; 64: 78-83. 4. Oliver RTD. Clues from natural history and results of treatment supporting the monoclonal ongin of germ cell tumours. Cancer Surveys 1990; 9: 332-68. 5. Oliver RTD Atrophy, hormones, genes and viruses in aetiology of germ cell tumours. Cancer Surveys 1990; 9: 263-86. 6 Blandy JP, Hope-Stone HF, Dayan AD. Tumours of the testicle. London: Heinemann, 1970. 7. Bloom DA. Two-step orchidopexy with pelviscopic clip ligation of the spermatic vessels. J Urol 1991; 145: 1030-33.
Monoclonal endotoxin antibody in
meningococcal sepsis SIR,-Dr Nadel and colleagues (March 14, p 678) raise several questions regarding the use of monoclonal endotoxin antibody (HA-lA) in meningococcal sepsis. We agree that only objectively analysed data from well-conducted clinical trials can serve as a solid basis for any (new) indication for any drug. For that reason Centocor is sponsoring the European, multicentre, randomised, placebo-controlled trial of HA-IA in children with fulminant meningococcal septicaemia. However, Nadel et al raise two issues that need to be addressed. Although both HA-IA and E5 are IgM monoclonal antibodies developed with the J5 mutant of Escherichia coli, their different xenogenicity and specificity properties have implications for efficacy and safety. HA-IA is a human antibody effective in gram-negative bacteraemia, especially in patients with shock.’ These findings have been confirmed in an open-label, multicentre trial. Since gram-negative bacteraemia is highly correlated with endotoxaemia,3these fmdings are entirely consistent with what
931
would be expected of an endotoxin antibody. The E5 results4 contradict this hypothesis, and the second E5 studyS did not confirm the efficacy suggested from post-hoc analysis of the first E5 trial. Therefore, there are no clinical data available to suggest that E5 has a real positive effect in patients. This should not be a surprise since E5 is a murine antibody that binds to a different epitope on the lipid A component of endotoxin. 6 Safety data on HA-1A (in more than 6000 patients, including 140 children) are very reassuring: adverse reactions (hypotension, urticaria) have been associated with the agent in less than 1 % of patients. As a large, xenogeneic protein, E5 would be expected to be strongly immunogenic when administered to man, and E5 does elicit a strong human anti-mouse (HAMA) response even after a single course of therapy in 40-50% of patients. Once induced, HAMA can also neutralise the effects of murine monoclonal antibody given therapeutically. HAMA can also induce type III hypersensitivity reactions, with the potential for development of serum sickness or anaphylaxis. The suggestion by Nadel et al that HA-IA might induce an increased release of inflammatory mediators is unfounded and not consistent with what we know of the mechanism of action of HA-lA.’ HA-IA specifically binds to and aggregates endotoxin. The complex fixes complement and binds via complement receptor 1 (only present on red blood cells of humans and primates) to human red blood cells and neutrophils. This is a major pathway for the clearance of IgM-antigen-complement complexes through the reticuloendothelial system. The complex can also be cleared by binding to neutrophils and subsequent internalisation. The net effect of these actions is to reduce the bioavailability of endotoxin. None of these events have been shown to increase the serum levels of any of the cytokines involved in the sepsis cascade.8 This is entirely consistent with the observed safety profile of the product. Centocor,
RONALD H. W. LORIJN
2300 AG Leiden, Netherlands
1. Ziegler EJ, Fisher CJ, Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991; 324: 429-88. 2. Smith CR. Anti-endotoxin antibodies: new clinical data. 12th International Symposium on Intensive Care and Emergency Medicine. (Brussels, March 24-27,
1992.)
RC, Ziegler EJ. HA-1A: a human monoclonal antibody for the of gram-negative sepsis. In: Young LS, Glauser MP, eds. Infect Dis Clin Am 1992 (March).
3 Smith CR, Straube treatment
N 4. Greenman
RL, Schein RMH, Martin MA, et al. A controlled clinical trial of E5 monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 1991; 266: 1097-126. 5. Wenzel R, Bone R, Fein A, et al. Results of s second double-blind, randomized, controlled trial of antiendotoxin antibody E5 in gram-negative sepsis. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (1991). 6. Bogard WC Jr, Daddona P, Damiano EM, et al. The human monoclonal antibody (MAb) HA-1A binds to endotoxin via an epitope in the lipid A domain of lipopolysaccharide (LPS). J Cell Biochem 1992; 16 C (suppl): 170. 7. Kneger JI, Fletcher RC, Siegel SA, et al. HA-1A (Centoxin) a human monoclonal IgM anti-endotoxin MAb mediates immune adherence of E coli J5 LPS via CR1 of human RBCs and neutrophils. J Cell Biochem 1992; 16C (suppl): 172. 8. Wortel CH, Ziegler EJ, Van Deventer SJH. Therapy of gram-negative sepsis m man with anti-endotoxin antibodies: a review. In: Sturk A, Van Deventer SJH, Ten Cate W, et al, eds. Bacterial endotoxins—cytokine mediators and new therapies for sepsis. New York: Wiley-Liss, 1991: 161-78. murine
sensitive
disc sensitivity testing. Therapy changed chloramphenicol 1 g 6-hourly but there was no improvement and she remained pyrexial and drowsy. Rifampicin was added 3 days after admission. She died 7 days later. The isolate had a minimum inhibitory concentration (MIC) to penicillin of 10 mg/1. The MIC to chloramphenicol was 2-0 mg/1 but the minimum bactericidal concentration (MBC) was 4-0 mg/l. Thus, despite apparent sensitivity of the strain by disc testing and MIC, the MBC showed the strain to be moderately resistant, on the criteria of Friedland and Klugman. Although this is our first reported experience with penicillinresistant pneumococcal meningitis in this area of north-west England, we have been monitoring the prevalence of penicillinresistant pneumococci since October, 1987.1 The prevalence of penicillin resistance in pneumococci isolated from clinical specimens (Whiston Hospital) has increased from 1-4% to 3-7%. Most resistant strains were from colonised children. However, for 12 of the 15 isolates from adults there was clinical infection. In only 2 of the early cases was there an association with foreign travel. Most strains (75%) were serotype 23, the rest being 6, 9, 14, 19, or 42. All strains (n 42) were multiply resistant: % resistant % resistant Agent Agent to
chloramphenicol
on
to
was
=
Penicillin Low level High level
Chloramphenicol Erythromycin Clarithromycin Azithromycin Rifampicin
100 Tetracycline 26 Trimethoprim 74 Sulphonamide 83 Vancomycin 7 Teicoplanin 7 7 0
Ceftriaxone Cefotaxime Ceftazidime
90 98 98 0 0 0 4 0
By contrast with the South African experience, a high proportion of our penicillin-resistant strains were also resistant to chloramphenicol (83%) and tetracycline (90%), so alternative agents are needed. Until this case of meningitis all the infections we had seen had been of the respiratory tract and had responded to erythromycin. Where strains are erythromycin-resistant, the newer macrolides clarithromycin and azithromycin are also inactive.2 Meningitis and infections caused by erythromycin-resistant strains are probably best treated with a third-generation cephalosporin, and over 95 % of our strains have been sensitive to cefotaxime, ceftazidime, and ceftriaxone. This case and those of Friedland and Klugman demonstrate the danger of reliance on disc zone sizes and MICs for chloramphenicol susceptibility testing of penicillin-resistant pneumococci. We agree that chloramphenicol should not be used for the treatment of penicillin-resistant pneumococcal meningitis. Department of Microbiology, Hospital,
Whiston
Prescot, L35 5DR, UK
Departments of Microbiology and Medicine, Walton Hospital,
Liverpool
Department of Medical Microbiology, Royal Liverpool University Hospital
E. J. RIDGWAY K. D. ALLEN T. J. NEAL M. LOMBARD A. RIGBY
Ridgway EJ, Allen KD, Galloway A, Rigby A, O’Donoghue M. Penicillin-resistant pneumococci in a Merseyside hospital. J Hosp Infect 1991; 17: 15-23. 2. Neal TJ, O’Donoghue MAT, Ridgway EJ, Allen KD. In-vitro activity of 10 antimicrobial agents against penicillin-resistant Streptococcus pneumoniae. J Antimicrob Chemother (in press). 1.
Penicillin-resistant pneumococcal
meningitis SIR,-Dr Friedland and Dr Klugman (Feb 15, p 405) report problems associated with penicillin-resistant pneumococcal
meningitis. A 73-year-old
woman was admitted in April, 1991, with confusion. She had a 1 week history of cough and dyspnoea for which she had been prescribed oral penicillin. Her temperature was 38°C and she was drowsy. The chest was normal. Her cerebrospinal fluid (CSF) contained 7200 white cells/ul (98% polymorphs) and protein 1-02 g/dl; glucose was not detected. Numerous gram-
positive diplococci were seen. The patient was given benzylpenicillin 24 megaunits daily. The following day, cultures of CSF and blood (taken on admission) yielded Streptococcus pneumoniae serotype 9, which was resistant to penicillin but
agree with Dr Friedland and Dr Klugman that chloramphenicol should not be used in the management of
SIR,-We
penicillin-resistant Streptococcus pneurrwniae meningitis. A 14-month-old child with meningitis was admitted to hospital. Gram-positive cocci were present in the CSF and penicillin 300 mg/kg daily and chloramphenicol 50 mg/kg were given. On the following day, Strep pneumoniae was isolated from the CSF and direct antibiotic sensitivity tests (Stokes method) suggested that the organism was sensitive to chloramphenicol but was probably moderately resistant to penicillin. It was decided to continue with chloramphenicol pending confirmation of the penicillin resistance. Moderate resistance to penicillin was confirmed the next day (MIC
and 62 survivors of myocardial infarction enrolled 3 months after the acute index event. A positive test for aPL was obtained in 3 (25%) TIA patients and in 8 (13%) myocardial infarction survivors. Blood samples for aPL measurement were obtained at least 3 months after the last ischaemic or necrotic event, so the increased aPL values in our patients were probably not due to the acute phase of tissue necrosis. During 24 months’ follow-up, three major thrombotic events (two in TIA patients and one in a myocardial infarction survivor) were seen in aPL-negative subjects, and none took place in the aPL-positive group. Our results are consistent with Sletnes and colleagues’ suggestion that aPL is not a risk factor for coronary or cerebrovascular thrombotic sequelae in patients with previous myocardial infarction or TIA.
Istituto di Medicina Interna, Milan University, 20122 Milano, Italy
MICHELE CORTELLARO CARLA BOSCHETTI MASSIMO CARDILLO TIZIANO BARBUI
The main investigators in the PLAT study are: Dr Michele Cortellaro, Dr Carlo Boschetti, Dr Elisabetta Cofrancesco, Dr Mariella Catalano, Dr Livio Gabrielli, Dr Giovanni de Gaetano, Dr Bruno Lombardi, Dr Guiseppe Specchta, Dr Luigi Tavazzi, Dr Elena Tremoli, and Dr Carlo Zanussi.
1. Hamsten A, Norberg R, Bjorkholm M, De Faire U, Holm G. Antibodies to cardiolipin m young survivors of myocardial infarction: an association with recurrent cardiovascular events. Lancet 1986; i: 113-16. 2. Cortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients. Atherosclerosis 1991; 90: 109-1 1.
Orchidopexy and transformation of seminoma to non-seminoma SIR,-Undescended testes are the only unequivocal risk factor for testicular germ-cell tumours.1 Whether surgical correction determines the histology of subsequent testicular tumours has received increasing attention.2,3 We have reviewed retrospectively patients with testes tumours who were referred to one of us (R.T.D.O.) during 1978-90. History of undescended testis, side of involvement, and operative correction, if any, was elicited by direct questioning of patients, and examination of hospital records and general practitioners’ notes. Histological findings for orchidectomy specimens or other tissues were reviewed by a second team of pathologists wherever possible. Of the 319 cases with adequate information, 119 were seminomas and 200 were malignant teratomas. 28 patients had a history of undescended testes (88%); in 7 of these, this was bilateral. 14 patients in the seminoma group and 14 in the malignant teratoma group had a positive history of undescended testes. 3 with seminoma and 10 with malignant teratoma had orchidopexy-2 and 10, respectively, on the same side as the subsequent tumour. Three-quarters of tumours in patients with uncorrected cryptorchidism were seminomas, whereas over 80% of tumours that developed after surgical correction were malignant teratomas (table). Of the patients with normally descended testes, 37% (119/319) had seminomas. No significant differences were detected between patients with stage 1 disease and those with metastatic disease, although there was a trend for more metastatic disease in patients with corrected cryptorchidism. The role of undescended testes in the pathogenesis of testicular tumours is yet to be defined. It is increasingly accepted that development of testicular cancer is a multistep process, going from carcinoma in situ through seminoma to malignant teratoma.4 Germinal epithelial atrophy has been postulated as the common pathway5 since it produces decreased feedback inhibition of the hypothalamus and increased gonadal hormonal drive, allowing less time for repair of DNA damage from environmental mutagens in the reduced number of germ cells. This hypothesis was based on the observation that many of the aetiologically associated risk factors for testicular tumours, whether intrinsic (genetic, hormonal) or extrinsic (trauma, viral infections, hormones), induced testicular atrophy. Several studies have suggested that vasectomy or operative correction of previous inguinal hernia, especially when complicated by haematoma,’* seem to increase the risk of subsequent malignant
EFFECT OF SURGICAL CORRECTION ON DEVELOPMENT OF TUMOURS IN PATIENTS WITH OR WITHOUT CRYPTORCHIDISM I
I
-
...
*p < 0 006, operated vs non-operated tall patients
disease, although the role of direct trauma remains controversial and .6 may merely draw the patient’s attention to that testis In this series, the 8-8% frequency of undescended testis is in
keeping with those of other studies. It is noteworthy that in the seminoma group with undescended testes, only 2 (15%) patients had corrective orchidopexy on the side of malignant disease, whereas in the non-seminoma group, nearly three-quarters (10 of 14) of patients with undescended testes had previous orchidopexy on that side. Other workers have also reported such findings (ref3 3 and Jones BJ et al, unpublished). These three studies suggest that operative correction of undescended testes increases the chances of subsequent malignant teratoma. Postoperative atrophy due to diminished vascular supply, with increased gonadotropin drive, could promote the transformation of seminoma to malignant teratoma. In view of the small number of cases involved, the results need to be interpreted with caution. Even if our fmdings are confirmed, it is clear that surgical correction of undescended testes should continue, in view of the psychological effects, ease of earlier diagnosis, and higher cure rate should malignant disease develop. However, perhaps more careful attention should be given at operation to vascular supply of the testes.’7 M. A. RAJA R. T. D. OLIVER D. BADENOCH Royal London Hospital, London E1 2AD, UK J. P. BLANDY C, Pike MC. Epidemiology of undescended testes. In: Oliver RTD, Blandy JP, Hope-Stone HF, eds. Oxford: Blackwell Scientific, 1989: 306-21. Pike MC, Chilvers C, Peckham MJ. Effect of age at orchidopexy on risk of testicular
1. Chilvers
2.
cancer. Lancet 1986; i 1246-48. 3. Halme A, Kellokumpu-Lehtinen P, Lehtonen T, Teppo L. Morphology of testicular germ cell tumours in treated and untreated cryptorchidism. Br J Urol 1989; 64: 78-83. 4. Oliver RTD. Clues from natural history and results of treatment supporting the monoclonal ongin of germ cell tumours. Cancer Surveys 1990; 9: 332-68. 5. Oliver RTD Atrophy, hormones, genes and viruses in aetiology of germ cell tumours. Cancer Surveys 1990; 9: 263-86. 6 Blandy JP, Hope-Stone HF, Dayan AD. Tumours of the testicle. London: Heinemann, 1970. 7. Bloom DA. Two-step orchidopexy with pelviscopic clip ligation of the spermatic vessels. J Urol 1991; 145: 1030-33.
Monoclonal endotoxin antibody in
meningococcal sepsis SIR,-Dr Nadel and colleagues (March 14, p 678) raise several questions regarding the use of monoclonal endotoxin antibody (HA-lA) in meningococcal sepsis. We agree that only objectively analysed data from well-conducted clinical trials can serve as a solid basis for any (new) indication for any drug. For that reason Centocor is sponsoring the European, multicentre, randomised, placebo-controlled trial of HA-IA in children with fulminant meningococcal septicaemia. However, Nadel et al raise two issues that need to be addressed. Although both HA-IA and E5 are IgM monoclonal antibodies developed with the J5 mutant of Escherichia coli, their different xenogenicity and specificity properties have implications for efficacy and safety. HA-IA is a human antibody effective in gram-negative bacteraemia, especially in patients with shock.’ These findings have been confirmed in an open-label, multicentre trial. Since gram-negative bacteraemia is highly correlated with endotoxaemia,3these fmdings are entirely consistent with what
931
would be expected of an endotoxin antibody. The E5 results4 contradict this hypothesis, and the second E5 studyS did not confirm the efficacy suggested from post-hoc analysis of the first E5 trial. Therefore, there are no clinical data available to suggest that E5 has a real positive effect in patients. This should not be a surprise since E5 is a murine antibody that binds to a different epitope on the lipid A component of endotoxin. 6 Safety data on HA-1A (in more than 6000 patients, including 140 children) are very reassuring: adverse reactions (hypotension, urticaria) have been associated with the agent in less than 1 % of patients. As a large, xenogeneic protein, E5 would be expected to be strongly immunogenic when administered to man, and E5 does elicit a strong human anti-mouse (HAMA) response even after a single course of therapy in 40-50% of patients. Once induced, HAMA can also neutralise the effects of murine monoclonal antibody given therapeutically. HAMA can also induce type III hypersensitivity reactions, with the potential for development of serum sickness or anaphylaxis. The suggestion by Nadel et al that HA-IA might induce an increased release of inflammatory mediators is unfounded and not consistent with what we know of the mechanism of action of HA-lA.’ HA-IA specifically binds to and aggregates endotoxin. The complex fixes complement and binds via complement receptor 1 (only present on red blood cells of humans and primates) to human red blood cells and neutrophils. This is a major pathway for the clearance of IgM-antigen-complement complexes through the reticuloendothelial system. The complex can also be cleared by binding to neutrophils and subsequent internalisation. The net effect of these actions is to reduce the bioavailability of endotoxin. None of these events have been shown to increase the serum levels of any of the cytokines involved in the sepsis cascade.8 This is entirely consistent with the observed safety profile of the product. Centocor,
RONALD H. W. LORIJN
2300 AG Leiden, Netherlands
1. Ziegler EJ, Fisher CJ, Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991; 324: 429-88. 2. Smith CR. Anti-endotoxin antibodies: new clinical data. 12th International Symposium on Intensive Care and Emergency Medicine. (Brussels, March 24-27,
1992.)
RC, Ziegler EJ. HA-1A: a human monoclonal antibody for the of gram-negative sepsis. In: Young LS, Glauser MP, eds. Infect Dis Clin Am 1992 (March).
3 Smith CR, Straube treatment
N 4. Greenman
RL, Schein RMH, Martin MA, et al. A controlled clinical trial of E5 monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 1991; 266: 1097-126. 5. Wenzel R, Bone R, Fein A, et al. Results of s second double-blind, randomized, controlled trial of antiendotoxin antibody E5 in gram-negative sepsis. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (1991). 6. Bogard WC Jr, Daddona P, Damiano EM, et al. The human monoclonal antibody (MAb) HA-1A binds to endotoxin via an epitope in the lipid A domain of lipopolysaccharide (LPS). J Cell Biochem 1992; 16 C (suppl): 170. 7. Kneger JI, Fletcher RC, Siegel SA, et al. HA-1A (Centoxin) a human monoclonal IgM anti-endotoxin MAb mediates immune adherence of E coli J5 LPS via CR1 of human RBCs and neutrophils. J Cell Biochem 1992; 16C (suppl): 172. 8. Wortel CH, Ziegler EJ, Van Deventer SJH. Therapy of gram-negative sepsis m man with anti-endotoxin antibodies: a review. In: Sturk A, Van Deventer SJH, Ten Cate W, et al, eds. Bacterial endotoxins—cytokine mediators and new therapies for sepsis. New York: Wiley-Liss, 1991: 161-78. murine
sensitive
disc sensitivity testing. Therapy changed chloramphenicol 1 g 6-hourly but there was no improvement and she remained pyrexial and drowsy. Rifampicin was added 3 days after admission. She died 7 days later. The isolate had a minimum inhibitory concentration (MIC) to penicillin of 10 mg/1. The MIC to chloramphenicol was 2-0 mg/1 but the minimum bactericidal concentration (MBC) was 4-0 mg/l. Thus, despite apparent sensitivity of the strain by disc testing and MIC, the MBC showed the strain to be moderately resistant, on the criteria of Friedland and Klugman. Although this is our first reported experience with penicillinresistant pneumococcal meningitis in this area of north-west England, we have been monitoring the prevalence of penicillinresistant pneumococci since October, 1987.1 The prevalence of penicillin resistance in pneumococci isolated from clinical specimens (Whiston Hospital) has increased from 1-4% to 3-7%. Most resistant strains were from colonised children. However, for 12 of the 15 isolates from adults there was clinical infection. In only 2 of the early cases was there an association with foreign travel. Most strains (75%) were serotype 23, the rest being 6, 9, 14, 19, or 42. All strains (n 42) were multiply resistant: % resistant % resistant Agent Agent to
chloramphenicol
on
to
was
=
Penicillin Low level High level
Chloramphenicol Erythromycin Clarithromycin Azithromycin Rifampicin
100 Tetracycline 26 Trimethoprim 74 Sulphonamide 83 Vancomycin 7 Teicoplanin 7 7 0
Ceftriaxone Cefotaxime Ceftazidime
90 98 98 0 0 0 4 0
By contrast with the South African experience, a high proportion of our penicillin-resistant strains were also resistant to chloramphenicol (83%) and tetracycline (90%), so alternative agents are needed. Until this case of meningitis all the infections we had seen had been of the respiratory tract and had responded to erythromycin. Where strains are erythromycin-resistant, the newer macrolides clarithromycin and azithromycin are also inactive.2 Meningitis and infections caused by erythromycin-resistant strains are probably best treated with a third-generation cephalosporin, and over 95 % of our strains have been sensitive to cefotaxime, ceftazidime, and ceftriaxone. This case and those of Friedland and Klugman demonstrate the danger of reliance on disc zone sizes and MICs for chloramphenicol susceptibility testing of penicillin-resistant pneumococci. We agree that chloramphenicol should not be used for the treatment of penicillin-resistant pneumococcal meningitis. Department of Microbiology, Hospital,
Whiston
Prescot, L35 5DR, UK
Departments of Microbiology and Medicine, Walton Hospital,
Liverpool
Department of Medical Microbiology, Royal Liverpool University Hospital
E. J. RIDGWAY K. D. ALLEN T. J. NEAL M. LOMBARD A. RIGBY
Ridgway EJ, Allen KD, Galloway A, Rigby A, O’Donoghue M. Penicillin-resistant pneumococci in a Merseyside hospital. J Hosp Infect 1991; 17: 15-23. 2. Neal TJ, O’Donoghue MAT, Ridgway EJ, Allen KD. In-vitro activity of 10 antimicrobial agents against penicillin-resistant Streptococcus pneumoniae. J Antimicrob Chemother (in press). 1.
Penicillin-resistant pneumococcal
meningitis SIR,-Dr Friedland and Dr Klugman (Feb 15, p 405) report problems associated with penicillin-resistant pneumococcal
meningitis. A 73-year-old
woman was admitted in April, 1991, with confusion. She had a 1 week history of cough and dyspnoea for which she had been prescribed oral penicillin. Her temperature was 38°C and she was drowsy. The chest was normal. Her cerebrospinal fluid (CSF) contained 7200 white cells/ul (98% polymorphs) and protein 1-02 g/dl; glucose was not detected. Numerous gram-
positive diplococci were seen. The patient was given benzylpenicillin 24 megaunits daily. The following day, cultures of CSF and blood (taken on admission) yielded Streptococcus pneumoniae serotype 9, which was resistant to penicillin but
agree with Dr Friedland and Dr Klugman that chloramphenicol should not be used in the management of
SIR,-We
penicillin-resistant Streptococcus pneurrwniae meningitis. A 14-month-old child with meningitis was admitted to hospital. Gram-positive cocci were present in the CSF and penicillin 300 mg/kg daily and chloramphenicol 50 mg/kg were given. On the following day, Strep pneumoniae was isolated from the CSF and direct antibiotic sensitivity tests (Stokes method) suggested that the organism was sensitive to chloramphenicol but was probably moderately resistant to penicillin. It was decided to continue with chloramphenicol pending confirmation of the penicillin resistance. Moderate resistance to penicillin was confirmed the next day (MIC
