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CURE OF PSEUDOMONAS AERUGINOSA INFECTION IN NEUTROPENIC PATIENTS BY CONTINUOUS INFUSION OF CEFTAZIDIME
937 UPDATED KIEL CLASSIFICATION
SIR,—We agree with Dr Mead and Dr Sweetenham (March 19, 649) that reproducibility and clinical relevance are important criteria in addition to biological accuracy by which pathological p
classifications may be judged. The modification of the Kiel classification with regard to T cell lymphoma to which they refer (Feb 6, p 292; March 12, p 603) is based on the results of histological and immunohistochemical observations made on many peripheral
lymphomas from China, England, Germany, and Japan.’ Preliminary data concerning the survival of patients with different subtypes of peripheral T cell lymphoma were presented in that study. Patients with the lymphoepithelial, angioimmunoblastic, and T zone subtypes had a better prognosis than did those with either the T-immunoblastic or pleomorphic variants. The comparison with "low grade" and "high grade" T cell lymphomas T cell
based on these findings. One of the main reasons for proposing the modification to the Kiel classification is to encourage pathologists to adopt uniform criteria for the diagnosis of T cell lymphomas. Only if this is done can the reproducibility and clinical relevance of the new scheme be adequately tested. A multicentre prospective clinicopathological study of T cell lymphomas has recently been started in the UK, which we hope will answer these important questions. was
Imperial Cancer Research Fund, Clinical Oncology Unit, Guy’s Hospital, London SE1 9RT
M. A. RICHARDS A. G. STANSFELD
therapy the plasma level of ceftazidime 1 h after the dose was 35 mg/1, and the trough level was 4 mg/l ; during continuous infusion the plasma level was 28 mg/1. The patient then improved rapidly while still granulocytopenic. These two cases show that continuous infusion of ceftazidime can more effective in eradicating severe pseudomonas infections in granulocytopenic patients than intermittent administration of the same and other antibiotics. A similar increase in antibiotic activity in neutropenic patients by continuous infusion has been suggested for aminoglycosides1.2 and cefamandole3but this regimen has not gained wide acceptance, probably because of practical problems in administration and a prevailing impression (partly incorrect) that modern antibiotics are very effective in conventional intermittent schedules even in immunocompromised patients.4 Also previous studies have not been unequivocally in favour of continuous dosing. Studies in animals5show that maintenance of adequate serum concentrations is critically important in the outcome of experimental infections in neutropenia. Achieving (by a loading dose) and then sustaining high drug levels by continuous infusion is only possible for drugs without serious toxicity. Perhaps continuous infusion should be reserved for antibiotics without a "post-antibiotic effect".7,8 Most experience in granulocytopenic patients has been with aminoglycosides, which have a good post-antibiotic effect against gram-negative microorganisms and Staphylococcus aureus.9Beta-lactam antibiotics generally do not show a postantibiotic effect against gram-negative microorganisms9,10 and are less toxic, which make them good candidates for continuous infusion. be
1. Suchi
T, Lennert K, Tu L-Y, et al. Histopathology and immunohistochemistry of peripheral T-cell lymphomas: a proposal for their classification.J Clin Pathol 1987;
40: 995-1015.
CURE OF PSEUDOMONAS AERUGINOSA INFECTION IN NEUTROPENIC PATIENTS BY CONTINUOUS INFUSION OF CEFTAZIDIME
SIR,-In granulocytopenic patients infection with gram-negative microorganisms remains life-threatening despite the introduction of antibiotics of extended spectrum. Ceftazidime is active against Enterobacteriaceae and Pseudomonadaceae in
granulocytopenic
when used as monotherapy, but failures still occur. We have successfully treated two patients with Pseudomonas aeruginosa infection with ceftazidime in continuous infusion after they had failed to respond to the same antibiotic in intermittent
patients,
even
dosing. A 30-year-old man with a 10-year history of aplastic anaemia and slowly progressive pancytopenia was admitted to hospital because of fever, chills, and skin lesions. Leucocyte count 0-4 x 109/1, platelets 16 x 109/1. He was treated with ticarcillin, tobramycin, and granulocyte transfusions. Ps aeruginosa sensitive to the above antibiotics was isolated and blood cultures soon became sterile and the fever disappeared. However, cultures from the skin lesions remained positive for Ps aeruginosa and new lesions appeared. Neither ticarcillin nor tobramycin could be detected in the cutaneous lesions, so after about 6 weeks ceftazidime 3 x 2 g daily replaced the former antibiotics but the patient did not improve. Some ceftazidime was detectable in the lesions but before the next infusion it had disappeared. So after 1 week of intermittent therapy ceftazidime was given as a continuous infusion of 6 g per day, after a loading dose of 2 g. From then on, the drug could be detected in the lesions continuously, and after 1 week of therapy all cultures were negative. The lesions healed rapidly. Ceftazidime was continued for 14 days because the granulocyte count remained below 0 1 x 109/1. A 46-year-old man with leukaemia was treated with chemotherapy and antibiotics for selective decontamination of the digestive tract. During the aplastic phase he became febrile and a skin lesion developed in the groin. He was treated with cephradine (3 x2 g), tobramycin (3 x 80 mg), and ticarcillin (4 x 5 g). After 3 days these were replaced by ceftazidime 3 x 2 g daily because the infection was worse even though Ps aeruginosa isolated from the skin lesion and from the blood showed good in-vitro susceptibility to the antibiotics. The patient remained febrile and the skin lesion did not heal. After 4 days of intermittent therapy, ceftazidime was given as a continuous infusion after a 2 g loading dose. During intermittent
Division of Haematology, Department of Medicine, and Laboratory of Medical University of Groningen, 9713 EZ Groningen, Netherlands
Microbiology,
S. DAENEN H. DE VRIES-HOSPERS
1. Feld R, Valdivieso M, Bodey GP, Rodriguez V. Comparison of amikacin and tobramycin in the treatment of infections in patients with cancer. J Infect Dis 1977; 135: 61-66. 2. Keating MJ, Bodey GP, Valdivieso M, Rodriguez V. A randomized comparative trial of three ammoglycosides: Comparison of continuous infusion of gentamicin, amikacin, and sisomycin combined with carbenicillin in the treatment of infections in neutropenic patients with malignancies. Medicine 1979, 58: 159-70. 3. Bodey GP, Ketchel SJ, Rodriguez V. A randomized study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. Am J Med 1979; 67: 608-16. 4 Love LJ, Schimpff SC, Schifer CA, Wiemik PH. Improved prognosis for granulocytopenic patients with gram-negative bacteremia. Am J Med 1980; 68: 643-48. 5. Roosendaal R, Bakker-Woudenberg IAJM, van den Berghe-van Raffe M, Michel MF. Continuous versus intermittent administration of ceftazidime m experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats Antimicrob Agents Chemother 1986; 30: 403-08. 6. Frimodt-Moller N, Benkon NN, Frolund-Thomsen V Experimental infection with Str pneumoniae in mice. correlation of m vitro activity and pharmacokinetic parameter with in vivo effect for 14 cephalosporins. J Infect Dis 1986; 154: 511-17. 7. Gerber AU, Craig WA, Brugger H-P, Feller C, Vastola AP, Brandel J. Impact of dosing intervals on activity of gentamicin and ticarcillin against Pseudomonas aeruginosa in granulocytopenic mice. J Infect Dis 1983; 147: 910-17 8. Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediat 1986; 108: 835-40. 9. Vogelman BS, Craig WA. Postantibiotic effect J Antimicrob Chemother 1985; 15 (suppl A). 37-46. 10. Bodey GP, Pan T. Effect of cephalothin on growth patterns of microorganisms. J Antibiot 1976; 29: 1092-95
PROBLEM WITH ASPIRIN AS ANTITHROMBOTIC AGENT IN CORONARY ARTERY DISEASE
SIR,—The preliminary results from the Ongoing Physicians Study, published in the New England Journal of Medicine on Jan 28, 1988, reveal a very significant reduction in myocardial infarction in physicians taking one 325 mg aspirin tablet every other day. This study, along with two studies in unstable angina,l,2 makes a convincing case for the beneficial effect of aspirin as an antithrombotic agent. However, protection was not complete; recent experimental data may explain this. Aspirin ingestion does not totally inhibit platelet function, and the inhibition effect can be reversed by adrenaline (epinephrine)Health
induced alpha-adrenergic-receptor modulation. We have demonstrated that acute platelet thrombi form periodically in
SIR,—We agree with Dr Mead and Dr Sweetenham (March 19, 649) that reproducibility and clinical relevance are important criteria in addition to biological accuracy by which pathological p
classifications may be judged. The modification of the Kiel classification with regard to T cell lymphoma to which they refer (Feb 6, p 292; March 12, p 603) is based on the results of histological and immunohistochemical observations made on many peripheral
lymphomas from China, England, Germany, and Japan.’ Preliminary data concerning the survival of patients with different subtypes of peripheral T cell lymphoma were presented in that study. Patients with the lymphoepithelial, angioimmunoblastic, and T zone subtypes had a better prognosis than did those with either the T-immunoblastic or pleomorphic variants. The comparison with "low grade" and "high grade" T cell lymphomas T cell
based on these findings. One of the main reasons for proposing the modification to the Kiel classification is to encourage pathologists to adopt uniform criteria for the diagnosis of T cell lymphomas. Only if this is done can the reproducibility and clinical relevance of the new scheme be adequately tested. A multicentre prospective clinicopathological study of T cell lymphomas has recently been started in the UK, which we hope will answer these important questions. was
Imperial Cancer Research Fund, Clinical Oncology Unit, Guy’s Hospital, London SE1 9RT
M. A. RICHARDS A. G. STANSFELD
therapy the plasma level of ceftazidime 1 h after the dose was 35 mg/1, and the trough level was 4 mg/l ; during continuous infusion the plasma level was 28 mg/1. The patient then improved rapidly while still granulocytopenic. These two cases show that continuous infusion of ceftazidime can more effective in eradicating severe pseudomonas infections in granulocytopenic patients than intermittent administration of the same and other antibiotics. A similar increase in antibiotic activity in neutropenic patients by continuous infusion has been suggested for aminoglycosides1.2 and cefamandole3but this regimen has not gained wide acceptance, probably because of practical problems in administration and a prevailing impression (partly incorrect) that modern antibiotics are very effective in conventional intermittent schedules even in immunocompromised patients.4 Also previous studies have not been unequivocally in favour of continuous dosing. Studies in animals5show that maintenance of adequate serum concentrations is critically important in the outcome of experimental infections in neutropenia. Achieving (by a loading dose) and then sustaining high drug levels by continuous infusion is only possible for drugs without serious toxicity. Perhaps continuous infusion should be reserved for antibiotics without a "post-antibiotic effect".7,8 Most experience in granulocytopenic patients has been with aminoglycosides, which have a good post-antibiotic effect against gram-negative microorganisms and Staphylococcus aureus.9Beta-lactam antibiotics generally do not show a postantibiotic effect against gram-negative microorganisms9,10 and are less toxic, which make them good candidates for continuous infusion. be
1. Suchi
T, Lennert K, Tu L-Y, et al. Histopathology and immunohistochemistry of peripheral T-cell lymphomas: a proposal for their classification.J Clin Pathol 1987;
40: 995-1015.
CURE OF PSEUDOMONAS AERUGINOSA INFECTION IN NEUTROPENIC PATIENTS BY CONTINUOUS INFUSION OF CEFTAZIDIME
SIR,-In granulocytopenic patients infection with gram-negative microorganisms remains life-threatening despite the introduction of antibiotics of extended spectrum. Ceftazidime is active against Enterobacteriaceae and Pseudomonadaceae in
granulocytopenic
when used as monotherapy, but failures still occur. We have successfully treated two patients with Pseudomonas aeruginosa infection with ceftazidime in continuous infusion after they had failed to respond to the same antibiotic in intermittent
patients,
even
dosing. A 30-year-old man with a 10-year history of aplastic anaemia and slowly progressive pancytopenia was admitted to hospital because of fever, chills, and skin lesions. Leucocyte count 0-4 x 109/1, platelets 16 x 109/1. He was treated with ticarcillin, tobramycin, and granulocyte transfusions. Ps aeruginosa sensitive to the above antibiotics was isolated and blood cultures soon became sterile and the fever disappeared. However, cultures from the skin lesions remained positive for Ps aeruginosa and new lesions appeared. Neither ticarcillin nor tobramycin could be detected in the cutaneous lesions, so after about 6 weeks ceftazidime 3 x 2 g daily replaced the former antibiotics but the patient did not improve. Some ceftazidime was detectable in the lesions but before the next infusion it had disappeared. So after 1 week of intermittent therapy ceftazidime was given as a continuous infusion of 6 g per day, after a loading dose of 2 g. From then on, the drug could be detected in the lesions continuously, and after 1 week of therapy all cultures were negative. The lesions healed rapidly. Ceftazidime was continued for 14 days because the granulocyte count remained below 0 1 x 109/1. A 46-year-old man with leukaemia was treated with chemotherapy and antibiotics for selective decontamination of the digestive tract. During the aplastic phase he became febrile and a skin lesion developed in the groin. He was treated with cephradine (3 x2 g), tobramycin (3 x 80 mg), and ticarcillin (4 x 5 g). After 3 days these were replaced by ceftazidime 3 x 2 g daily because the infection was worse even though Ps aeruginosa isolated from the skin lesion and from the blood showed good in-vitro susceptibility to the antibiotics. The patient remained febrile and the skin lesion did not heal. After 4 days of intermittent therapy, ceftazidime was given as a continuous infusion after a 2 g loading dose. During intermittent
Division of Haematology, Department of Medicine, and Laboratory of Medical University of Groningen, 9713 EZ Groningen, Netherlands
Microbiology,
S. DAENEN H. DE VRIES-HOSPERS
1. Feld R, Valdivieso M, Bodey GP, Rodriguez V. Comparison of amikacin and tobramycin in the treatment of infections in patients with cancer. J Infect Dis 1977; 135: 61-66. 2. Keating MJ, Bodey GP, Valdivieso M, Rodriguez V. A randomized comparative trial of three ammoglycosides: Comparison of continuous infusion of gentamicin, amikacin, and sisomycin combined with carbenicillin in the treatment of infections in neutropenic patients with malignancies. Medicine 1979, 58: 159-70. 3. Bodey GP, Ketchel SJ, Rodriguez V. A randomized study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. Am J Med 1979; 67: 608-16. 4 Love LJ, Schimpff SC, Schifer CA, Wiemik PH. Improved prognosis for granulocytopenic patients with gram-negative bacteremia. Am J Med 1980; 68: 643-48. 5. Roosendaal R, Bakker-Woudenberg IAJM, van den Berghe-van Raffe M, Michel MF. Continuous versus intermittent administration of ceftazidime m experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats Antimicrob Agents Chemother 1986; 30: 403-08. 6. Frimodt-Moller N, Benkon NN, Frolund-Thomsen V Experimental infection with Str pneumoniae in mice. correlation of m vitro activity and pharmacokinetic parameter with in vivo effect for 14 cephalosporins. J Infect Dis 1986; 154: 511-17. 7. Gerber AU, Craig WA, Brugger H-P, Feller C, Vastola AP, Brandel J. Impact of dosing intervals on activity of gentamicin and ticarcillin against Pseudomonas aeruginosa in granulocytopenic mice. J Infect Dis 1983; 147: 910-17 8. Vogelman B, Craig WA. Kinetics of antimicrobial activity. J Pediat 1986; 108: 835-40. 9. Vogelman BS, Craig WA. Postantibiotic effect J Antimicrob Chemother 1985; 15 (suppl A). 37-46. 10. Bodey GP, Pan T. Effect of cephalothin on growth patterns of microorganisms. J Antibiot 1976; 29: 1092-95
PROBLEM WITH ASPIRIN AS ANTITHROMBOTIC AGENT IN CORONARY ARTERY DISEASE
SIR,—The preliminary results from the Ongoing Physicians Study, published in the New England Journal of Medicine on Jan 28, 1988, reveal a very significant reduction in myocardial infarction in physicians taking one 325 mg aspirin tablet every other day. This study, along with two studies in unstable angina,l,2 makes a convincing case for the beneficial effect of aspirin as an antithrombotic agent. However, protection was not complete; recent experimental data may explain this. Aspirin ingestion does not totally inhibit platelet function, and the inhibition effect can be reversed by adrenaline (epinephrine)Health
induced alpha-adrenergic-receptor modulation. We have demonstrated that acute platelet thrombi form periodically in