- Email: [email protected]
13th International Congress of Chemotherapy, August 28 to September 2, 1983, Vienna, Austria
THE ANTIMICROBIC NEWSLETTER, FEBRUARY 1984
was presented in session SE4.2/15. This new monocyclic/3-1actam compares favorably in vitro and in vivo to aztreonam. The compound has no gram-positive activity (SE4.2/15-1) and appears slightly superior to aztreonam in the mouse protection model. H u m a n protein binding is 28%, one-half the level of aztreonam. Its half-life is 1.8 hr and 85% of the drug is excreted in the urine. RO 17-2301 seems stable to more 13-1actamases, especially type IV K1, than aztreonam and one-dilution more potent against P. aeruginosa. Session 4.2/15 also contained early reports on CM40874. The drug is
17
among the most/3-1actamase stable ]3-1actams, having hydrolysis rates comparable to cefoxitin and moxalactam. Its MIC00 activity was ~ 1.0 ~g/ml for Enterobacteriaceae, 13.7 tzg/ml for P. aeruginosa, but 224/~g/ml for S. aureus. KIT-180 (formerly KI-6269) is a new cefoperazone-like drug projected for treatment of Pseudomonas and other infections. Preliminary data was presented by Kantoishi Pharmaceuticals Co, Tokyo, Japan. Cefbuperazone (TI982) is a 7methoxy cefoperazone-like drug. Like other cephamycins it is ]3-1actamase stable, has a t,/, of 1.7 hr and a
spectrum that includes Enterobacteriaceae, gram-positive cocci, and nearly all anaerobes. Preliminary reports for biliary and Ob/Gyn infections were promising. Cefbuperazone is a development of Toyama recently licensed to Bristol Laboratories in the USA. ISF3453 is a new o~-hydroxyimino-oxocephalosporin produced by ISF Laboratories for BioMedical Research, Milan, Italy. Data was very preliminary, but it appears/3lactamase stable and has favorable pharmacokinetics in animals.
antimicrobial prophylaxis of bacterial infection. The center of attention was a summary of the most recent antimicrobial therapy trial for empiric treatment of bacterial infections. Dr. Harold Gaya, a member of the Steering Committee of the EORTC Antimicrobial Therapy Project Group presented the results in the third antimicrobial collaborative study since the inception of prospective studies in 1974. The first EORTC trial showed similar therapeutic results using any of three initial therapeutic regimens (carbenicillin/gentamicin, cephalothin]gentamicin, carbenicillin/cephalothin), but concluded that cephalothin potentiated the nephrotoxicity of gentamicin. The second therapeutic study of the EORTC focused on the question of whether three antimicrobial agents given initially to the neutropenic cancer patient result in better clinical results than two. That
study failed to demonstrate that cefazolin added to carbenicillin plus amikacin improved the initial clinical response rates over carbenicillin/ amikacin. The third EORTC trial is the largest study completed to date. Initially, 877 patients were randomized, from which 742 were considered eligible for therapy and 642 found to have documented or possible bacterial infections. The reduction in numbers of evaluable cases was related primarily to the presence of viral or fungal infections. Of the 582 cases deemed evaluable, 370 were so-called "possible" or clinically documented infections, 212 were documented bacterial processes. Fifty-eight infections were nonbacterial and 12 were due to multiple pathogens. One hundred and fiftyfour bacteremias were documented, of which 142 were due to a single pathogen. There were 85 gram-
R. N. J O N E S
SYMPOSIA REVIEW
Management of Infections in Cancer Patients. A concluding session of the 13th International Congress of Chemotherapy was devoted to the subject of management of infections in cancer patients, sponsored by the European Organization for the Research and Treatment of Cancer (EORTC) Antimicrobial Therapy Project Group. EORTC actually includes a number of American hospitals and institutions in the Middle East as well as Europe. One of its purposes is to organize controlled collaborative studies that evaluate different regimens for prevention and therapy of infection in immunosuppressed cancer patients. A variety of topics was covered during this symposium, including the use of therapeutic and prophylactic white cell transfusions, viral and parasitic infections in the compromised host, prophylaxis and treatment of fungal disease, and
0738-1751/84J$0.00+2.00
O 1984 BY ELSEVIER SCIENCE PUBLISHING CO., INC.
18
negative pathogens and 57 grampositive pathogens. A most important feature of the clinical design was the randomization of neutropenic patients to one of three groups, in which the common component of therapy was amikacin. The patients additionally received one of three/~-lactam agents: azlocillin, cefotaxime, or ticarcillin. Forty-seven percent of the patients had acute myelocytic leukemia and 63% of the total had acute leukemia. Of the bacteremias, the response rate was 65% of 51 bacteremias in the patients receiving azlocillin, 42% of 43 bacteremias in the patients receiving cefotaxime, and 43% of 60 individuals receiving ticarcillin. A little more than one-half of the single gram-negative bacteremias responded, 51% of the total of 85. The patients w h o received azlocillin had a 64% response rate out of 33 for gram-negative rod infections in contrast to 35% of 20 and 47% of 32 responses of gram-negative bacteremias with cefotaxime and ticarcillin, respectively. The response rate in gram-positive bacteremias was 67% in the first group, 45% in the second group, and 32% in the third group. Azlocillin plus amikacin was significantly better than the other regimens for both gram-positive and gram-negative bacteremias. Of particular interest were the Pseudomonas aeruginosa septicemias. Seven of 10 or 70% were cured receiving azlocillinlamikacin, but 0 out of 5 w h o received cefotaxime/amikacin responded and 63% of 8 who received ticarcillin/amikacin responded. The results were poor for n o n p s e u d o m o n a d infections treated with ticarcillin and amikacin. Of E. coli infections, 81% of 11 E. coli septicemias were cured with azlocillin plus amikacin, vs 45% of 11 receiving cefotaxime plus amikacin, and 47% of 17 receiving ticarcillin plus amikacin. Patient management factors were comparable in all treatment groups, and there appeared to be no difference in host factors, which ac-
THE ANTIMICROBIC NEWSLETTER, FEBRUARY 1984
counted for the poorer responses in the patients receiving either cefotaxime or ticarcillin vs azlocillin plus amikacin. In the first EORTC trial, 6 out of 7 patients w h o received carbenicillin plus gentamicin for Pseudornonas septicemias were cured, as opposed to 0 out of 5 w h o received cephalothin plus gentamicin. There is a consistent theme that recurs in the EORTC studies: a simple active agent does not represent optimal antipseudomonal activity. The best results forP. aeruginosa infections are obtained with an antipseudomonal penicillin and aminoglycoside. This EORTC trial is the first to demonstrate a statistically significant difference in efficacy between one regimen group vs another. Large numbers of patients and large numbers of bacteremic infection (both the gram-positive and the gram-negative type) make this probably the largest study of its kind to be conducted in high-risk immunosuppressed subjects.
Interferon--The First Quarter Century. A main lecture was delivered at the International Congress of Chemotherapy by Dr. Thomas C. Merigan, Chief of the Division of Infectious Diseases at Stanford University School of Medicine, Palo Alto, CA. Dr. Merigan's lecture was entitled, "Interferon--The First Quarter Century." He noted that until recently, shortages of interferon for clinical trials has limited its application as a potential therapeutic agent for viral diseases and neoplastic processes in humans. Early studies were carried out with human leukocyte interferon prepared by crude and tedious processes. Recombinant DNA technology has now insured adequate quantities of materials for pilot studies in largescale human trial. To date, a-recombinant interferon is plentiful and there are other preparations such as ~- or immune interferon that may become available soon for therapeutic and prophylactic use.
"© 1984 BY ELSEVIER SCIEN(~E PUBLISHING CO., INC.
Earlier studies showed that beneficial effects were achieved when crude interferon preparations were instilled into the eye for herpetic infection. Nonetheless, this approach is no more effective than a number of antiviral chemicals applied topically. The observation of a prophylactic effect in rhinovirus infection in volunteers a decade ago has yet to be matched by any other available antiviral agent. In randomized doubleblind placebo-control trials, several human herpes viruses, including herpes simplex and varicella zoster, appear susceptible to interferon therapy in both immunosuppressed and normal subjects. Even cytomegaloviruses (CMV) showed some susceptibility to interferon in terms of cessation of peripheral virus shedding and as a prophylactic agent in preventing CMV infections in renal transplants. It must be acknowledged that no important activity has been shown of interferon on established disease such as advanced cytomegalovirus pneumonia. Chronic hepatitis B virus infections also show some responsiveness to leukocyte interferon in open trials. Long-term randomized placebo-control studies have been initiated to assess the impact of interferon in conjunction with vidarabine. These studies were carried out with relatively crude interferon preparations (0.01% and 0.1%) leukocyte interferon made by the Finnish Red Cross. The current explosion in bacterial cloning in recombinant DNA technology has been applied in a number of laboratories. The normal function of multiple c~-interferon genes that have been discovered through these cloning techniques has not yet been determined. At least 22 genes have been identified and seem to have functions. An important question is whether interferon genes code for host defense or regulatory proteins, each acting on defined sites. In the two years since they have
0738-1751/84/$0.00+2.00
THE ANTIMICROBIC NEWSLETTER, FEBRUARY 1984
become available, relatively pure preparations of recombinant interferon have been given to patients with a variety of cancers, chronic hepatitis, and rhinovirus infection. In all three of these settings the o~-2 interferon species seemed to be beneficial, comparable to the natural c~-interferons, which represent a pool of ten or more o~ species produced in leukocytes. Unfortunately, the major side effects of interferon including fever, malaise, and bone marrow suppression, also have been observed in subjects given the pure biosynthetic material. A few cancers have shown objective response and current studies have combined interferon with cytoreductive chemotherapy. One of the important issues with interferon for rhinovirus (common colds) is whether or not it will have an effect relatively late in the course of the disease. Future directions for clinical trials with interferon include herpes genitalis and herpes labialis, systemic CMV and EBV infections, rabies and other central nervous system viral
0738-1751/84/$0.00+2.00
19
infections, influenza, adenovirus, chronic hepatitis B, papovavirus, and herpes zoster in immunosuppressed patients. Studies with juvenile laryngeal papilloma viruses are also being planned. Currently, there is no available therapy for agents like Ebola-Marburg agents, rabies, and the hemolytic fevers. Other diseases for which there is possibly a viral etiology, ie, multiple sclerosis, amyotropic lateral sclerosis, and certain forms of arthritis, need to be considered and might be appropriate for therapeutic trials. There are many questions about the tissue specificity of the interferon and the immunoregulatory role of this fascinating group of compounds. Because interferon is produced as a normal response to viral infections and malignant cells, it seems important to identify any potential postinterferon deficiencies or to start therapy before endogenous interferons are produced. Then, the agent may have a more optimal effect. Combination chemo-
therapy with antineoplastic or other antiviral agents is also an opportune area for further studies. There is preliminary evidence from in vitro and in vivo animal model systems, particularly with the y-interferon species, that there are at least additive and perhaps synergistic effects with each other against both cancer and infectious diseases. Irrespective of the role of interferon clinically in the understanding of alteration of human disease, DNA cloning technology has made a major medical contribution. Dr. Merigan cautioned against too much enthusiasm for the potential of biotechnology in human medicine. The impact of this newer technology will probably come too slowly for some enthusiasts, but there is no doubt that many fields of medicine will be influenced by the new recombinant approaches to production of interferon and interferon may have some effect on a wide variety of human disease processes. L. S. Y O U N G
O 1984 BY ELSEVIER SCIENCE PUBLISHING CO., INC.
was presented in session SE4.2/15. This new monocyclic/3-1actam compares favorably in vitro and in vivo to aztreonam. The compound has no gram-positive activity (SE4.2/15-1) and appears slightly superior to aztreonam in the mouse protection model. H u m a n protein binding is 28%, one-half the level of aztreonam. Its half-life is 1.8 hr and 85% of the drug is excreted in the urine. RO 17-2301 seems stable to more 13-1actamases, especially type IV K1, than aztreonam and one-dilution more potent against P. aeruginosa. Session 4.2/15 also contained early reports on CM40874. The drug is
17
among the most/3-1actamase stable ]3-1actams, having hydrolysis rates comparable to cefoxitin and moxalactam. Its MIC00 activity was ~ 1.0 ~g/ml for Enterobacteriaceae, 13.7 tzg/ml for P. aeruginosa, but 224/~g/ml for S. aureus. KIT-180 (formerly KI-6269) is a new cefoperazone-like drug projected for treatment of Pseudomonas and other infections. Preliminary data was presented by Kantoishi Pharmaceuticals Co, Tokyo, Japan. Cefbuperazone (TI982) is a 7methoxy cefoperazone-like drug. Like other cephamycins it is ]3-1actamase stable, has a t,/, of 1.7 hr and a
spectrum that includes Enterobacteriaceae, gram-positive cocci, and nearly all anaerobes. Preliminary reports for biliary and Ob/Gyn infections were promising. Cefbuperazone is a development of Toyama recently licensed to Bristol Laboratories in the USA. ISF3453 is a new o~-hydroxyimino-oxocephalosporin produced by ISF Laboratories for BioMedical Research, Milan, Italy. Data was very preliminary, but it appears/3lactamase stable and has favorable pharmacokinetics in animals.
antimicrobial prophylaxis of bacterial infection. The center of attention was a summary of the most recent antimicrobial therapy trial for empiric treatment of bacterial infections. Dr. Harold Gaya, a member of the Steering Committee of the EORTC Antimicrobial Therapy Project Group presented the results in the third antimicrobial collaborative study since the inception of prospective studies in 1974. The first EORTC trial showed similar therapeutic results using any of three initial therapeutic regimens (carbenicillin/gentamicin, cephalothin]gentamicin, carbenicillin/cephalothin), but concluded that cephalothin potentiated the nephrotoxicity of gentamicin. The second therapeutic study of the EORTC focused on the question of whether three antimicrobial agents given initially to the neutropenic cancer patient result in better clinical results than two. That
study failed to demonstrate that cefazolin added to carbenicillin plus amikacin improved the initial clinical response rates over carbenicillin/ amikacin. The third EORTC trial is the largest study completed to date. Initially, 877 patients were randomized, from which 742 were considered eligible for therapy and 642 found to have documented or possible bacterial infections. The reduction in numbers of evaluable cases was related primarily to the presence of viral or fungal infections. Of the 582 cases deemed evaluable, 370 were so-called "possible" or clinically documented infections, 212 were documented bacterial processes. Fifty-eight infections were nonbacterial and 12 were due to multiple pathogens. One hundred and fiftyfour bacteremias were documented, of which 142 were due to a single pathogen. There were 85 gram-
R. N. J O N E S
SYMPOSIA REVIEW
Management of Infections in Cancer Patients. A concluding session of the 13th International Congress of Chemotherapy was devoted to the subject of management of infections in cancer patients, sponsored by the European Organization for the Research and Treatment of Cancer (EORTC) Antimicrobial Therapy Project Group. EORTC actually includes a number of American hospitals and institutions in the Middle East as well as Europe. One of its purposes is to organize controlled collaborative studies that evaluate different regimens for prevention and therapy of infection in immunosuppressed cancer patients. A variety of topics was covered during this symposium, including the use of therapeutic and prophylactic white cell transfusions, viral and parasitic infections in the compromised host, prophylaxis and treatment of fungal disease, and
0738-1751/84J$0.00+2.00
O 1984 BY ELSEVIER SCIENCE PUBLISHING CO., INC.
18
negative pathogens and 57 grampositive pathogens. A most important feature of the clinical design was the randomization of neutropenic patients to one of three groups, in which the common component of therapy was amikacin. The patients additionally received one of three/~-lactam agents: azlocillin, cefotaxime, or ticarcillin. Forty-seven percent of the patients had acute myelocytic leukemia and 63% of the total had acute leukemia. Of the bacteremias, the response rate was 65% of 51 bacteremias in the patients receiving azlocillin, 42% of 43 bacteremias in the patients receiving cefotaxime, and 43% of 60 individuals receiving ticarcillin. A little more than one-half of the single gram-negative bacteremias responded, 51% of the total of 85. The patients w h o received azlocillin had a 64% response rate out of 33 for gram-negative rod infections in contrast to 35% of 20 and 47% of 32 responses of gram-negative bacteremias with cefotaxime and ticarcillin, respectively. The response rate in gram-positive bacteremias was 67% in the first group, 45% in the second group, and 32% in the third group. Azlocillin plus amikacin was significantly better than the other regimens for both gram-positive and gram-negative bacteremias. Of particular interest were the Pseudomonas aeruginosa septicemias. Seven of 10 or 70% were cured receiving azlocillinlamikacin, but 0 out of 5 w h o received cefotaxime/amikacin responded and 63% of 8 who received ticarcillin/amikacin responded. The results were poor for n o n p s e u d o m o n a d infections treated with ticarcillin and amikacin. Of E. coli infections, 81% of 11 E. coli septicemias were cured with azlocillin plus amikacin, vs 45% of 11 receiving cefotaxime plus amikacin, and 47% of 17 receiving ticarcillin plus amikacin. Patient management factors were comparable in all treatment groups, and there appeared to be no difference in host factors, which ac-
THE ANTIMICROBIC NEWSLETTER, FEBRUARY 1984
counted for the poorer responses in the patients receiving either cefotaxime or ticarcillin vs azlocillin plus amikacin. In the first EORTC trial, 6 out of 7 patients w h o received carbenicillin plus gentamicin for Pseudornonas septicemias were cured, as opposed to 0 out of 5 w h o received cephalothin plus gentamicin. There is a consistent theme that recurs in the EORTC studies: a simple active agent does not represent optimal antipseudomonal activity. The best results forP. aeruginosa infections are obtained with an antipseudomonal penicillin and aminoglycoside. This EORTC trial is the first to demonstrate a statistically significant difference in efficacy between one regimen group vs another. Large numbers of patients and large numbers of bacteremic infection (both the gram-positive and the gram-negative type) make this probably the largest study of its kind to be conducted in high-risk immunosuppressed subjects.
Interferon--The First Quarter Century. A main lecture was delivered at the International Congress of Chemotherapy by Dr. Thomas C. Merigan, Chief of the Division of Infectious Diseases at Stanford University School of Medicine, Palo Alto, CA. Dr. Merigan's lecture was entitled, "Interferon--The First Quarter Century." He noted that until recently, shortages of interferon for clinical trials has limited its application as a potential therapeutic agent for viral diseases and neoplastic processes in humans. Early studies were carried out with human leukocyte interferon prepared by crude and tedious processes. Recombinant DNA technology has now insured adequate quantities of materials for pilot studies in largescale human trial. To date, a-recombinant interferon is plentiful and there are other preparations such as ~- or immune interferon that may become available soon for therapeutic and prophylactic use.
"© 1984 BY ELSEVIER SCIEN(~E PUBLISHING CO., INC.
Earlier studies showed that beneficial effects were achieved when crude interferon preparations were instilled into the eye for herpetic infection. Nonetheless, this approach is no more effective than a number of antiviral chemicals applied topically. The observation of a prophylactic effect in rhinovirus infection in volunteers a decade ago has yet to be matched by any other available antiviral agent. In randomized doubleblind placebo-control trials, several human herpes viruses, including herpes simplex and varicella zoster, appear susceptible to interferon therapy in both immunosuppressed and normal subjects. Even cytomegaloviruses (CMV) showed some susceptibility to interferon in terms of cessation of peripheral virus shedding and as a prophylactic agent in preventing CMV infections in renal transplants. It must be acknowledged that no important activity has been shown of interferon on established disease such as advanced cytomegalovirus pneumonia. Chronic hepatitis B virus infections also show some responsiveness to leukocyte interferon in open trials. Long-term randomized placebo-control studies have been initiated to assess the impact of interferon in conjunction with vidarabine. These studies were carried out with relatively crude interferon preparations (0.01% and 0.1%) leukocyte interferon made by the Finnish Red Cross. The current explosion in bacterial cloning in recombinant DNA technology has been applied in a number of laboratories. The normal function of multiple c~-interferon genes that have been discovered through these cloning techniques has not yet been determined. At least 22 genes have been identified and seem to have functions. An important question is whether interferon genes code for host defense or regulatory proteins, each acting on defined sites. In the two years since they have
0738-1751/84/$0.00+2.00
THE ANTIMICROBIC NEWSLETTER, FEBRUARY 1984
become available, relatively pure preparations of recombinant interferon have been given to patients with a variety of cancers, chronic hepatitis, and rhinovirus infection. In all three of these settings the o~-2 interferon species seemed to be beneficial, comparable to the natural c~-interferons, which represent a pool of ten or more o~ species produced in leukocytes. Unfortunately, the major side effects of interferon including fever, malaise, and bone marrow suppression, also have been observed in subjects given the pure biosynthetic material. A few cancers have shown objective response and current studies have combined interferon with cytoreductive chemotherapy. One of the important issues with interferon for rhinovirus (common colds) is whether or not it will have an effect relatively late in the course of the disease. Future directions for clinical trials with interferon include herpes genitalis and herpes labialis, systemic CMV and EBV infections, rabies and other central nervous system viral
0738-1751/84/$0.00+2.00
19
infections, influenza, adenovirus, chronic hepatitis B, papovavirus, and herpes zoster in immunosuppressed patients. Studies with juvenile laryngeal papilloma viruses are also being planned. Currently, there is no available therapy for agents like Ebola-Marburg agents, rabies, and the hemolytic fevers. Other diseases for which there is possibly a viral etiology, ie, multiple sclerosis, amyotropic lateral sclerosis, and certain forms of arthritis, need to be considered and might be appropriate for therapeutic trials. There are many questions about the tissue specificity of the interferon and the immunoregulatory role of this fascinating group of compounds. Because interferon is produced as a normal response to viral infections and malignant cells, it seems important to identify any potential postinterferon deficiencies or to start therapy before endogenous interferons are produced. Then, the agent may have a more optimal effect. Combination chemo-
therapy with antineoplastic or other antiviral agents is also an opportune area for further studies. There is preliminary evidence from in vitro and in vivo animal model systems, particularly with the y-interferon species, that there are at least additive and perhaps synergistic effects with each other against both cancer and infectious diseases. Irrespective of the role of interferon clinically in the understanding of alteration of human disease, DNA cloning technology has made a major medical contribution. Dr. Merigan cautioned against too much enthusiasm for the potential of biotechnology in human medicine. The impact of this newer technology will probably come too slowly for some enthusiasts, but there is no doubt that many fields of medicine will be influenced by the new recombinant approaches to production of interferon and interferon may have some effect on a wide variety of human disease processes. L. S. Y O U N G
O 1984 BY ELSEVIER SCIENCE PUBLISHING CO., INC.