Addendum
A. A. Fauser, E. Lang, G. D61ken, K. J. Bross, J. Schmid, F. S6rgel
Treatment of Severe Sepsis in Bone Marrow Transplant Recipients with Teicoplanin in Combination with [5-Lactams and Aminoglycosides Summary: We evaluated teicoplanin for suspected gram-positive infections after inadequate response to initial empiric beta-lactam and aminoglycoside combination therapy. All 20 patients included in this study received either an allogeneic (8 patients) or an autologous (12 patients) bone marrow transplant for acute myeloid leucaemia (AML), non-Hodgkin's-lymphoma (NHL, high grade) or other malignant diseases. All patients developing primary septicaemia of unknown origin (18 patients) or catheter-related septicaemia (2 patients) were treated with 400 mg teicoplanin, administered i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g i.v., t.i.d.;
netilmicin 400 mg once daily). All patients responded to therapy, 19 patients were clinically cured and one patient improved under therapy. The therapeutic regimen was well tolerated; only one adverse drug reaction was observed. We did not observe any delayed take or prolonged neutropenia or thrombocytopenia with this therapeutic regimen when our patients were compared to other bone marrow transplant patients (who did not receive this antimicrobiat therapy). Our results suggest that teicoplanin is a potentially effective and well tolerated antimicrobial agent in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides.
Zusammenfassung: Teicoplanin in Kombination mit ~-Laktamen und Aminoglykosiden bei Knochenmarktransplantatempffdngern mit schwerer Sepsis. Wir unter-
on mit einem Cephalosporin und einem Aminoglykosid (Ceftazidim 2 g i.v., 3 x/die, Netilmicin 400 mg, 1 x/die). Alle behandelten Patienten sprachen auf diese Therapie an. 19 Patienten wurden klinisch geheilt, ein Patient besserte sich unter dieser Therapie. Die Kombinationstherapie wurde gut vertragen, unerwiinschte Arzneimittelwirkungen traten w/ihrend der Studie nicht auf. Wir beobachteten kein verz6gertes Angehen des Knochenmarks oder eine Verl/ingerung der Thrombozytopenie unter dieser Behandlung im Vergleich zu anderen knochenmarktransplantierten Patienten, die diese antimikrobielle Behandlung nicht erhielten. Unsere Ergebnisse zeigen, dab Teicoplanin ein wirksames und gut Vertr/igliches Antibiotikum fiir knochenmarktransplantierte Patienten ist, die prim~ir nicht auf die Kombinationstherapie mit [~-Laktam-Antibiotika und Aminoglykosiden ansprechen.
suchten Teicoplanin bei vermuteten grampositiven Infektionen nach ungeniigendem Ansprechen auf die anf/ingliche Kombinationstherapie von ~-Laktam-Antibiotika und Aminoglykosiden. Alle 20 in dieser Studie erfaBten Patienten wurden entweder allogen (8 Patienten) oder autolog (12 Patienten) transplantiert mit folgenden Grundkrankheiten: akute myeloische Leuk/imie (AML), Non-Hodgldn-Lymphom (NHL) oder andere maligne Erkrankungen. Alle Patienten, die eine prim~ire Septik/imie unbekannten Ursprungs entwickelten (18 Patienten) oder unter einer Katheter-bedingten Septik~imie (2 Patienten) litten, wurden mit 400 mg Teicoplanin behandelt. Die Verabreichung von Teicoplanin erfolgte einmal t/iglich intraven6s in Kombinati-
Introduction Granulocytopenic patients, especially those receiving a bone marrow transplant, present special therapeutic problems, since infections with gram- positive microorganisms are an increasing cause of morbidity and mortality [1, 2]. Patients receiving a bone marrow transplant (BMT) are exposed to long-term use o f central venous catheters, which is considered to be one of the factors responsible for the increased infection rate; additional factors include existing neutropenia with granulocyte counts below 100/mm3 and the inflammation of mucous membranes, which lowers local defense mechanisms [3]. Numerous efforts have been made to decrease the incidence of febrile episodes in patients following BMT. Since many causative gram-positive microorganisms show resistance to beta-lactams and aminoglycosides, it seems resonable to include a highly ac-
tive anti-gram-positive agent such as teicoplanin in the standard antimicrobial regimen. Teicoplanin is a new glycopeptide antibiotic active against gram-positive microorganisms, e.g. staphylococci including strains resistant to methicillin, streptococci including enterococci and pneumococci, corynebacteria group J K , and anaerobic organisms including Clostridium difficile [4]. The pharmacokinetics of teicoplanin permit a once-daily administration either intravenously, as bolus or infusion, or intramuscularly [5, 6]. It is bactericidal through inhibition of the peptidoglycane-elongation in the bacterial cell wall Prof. Dr. A. A. Fauser, Prof. Dr. G. Di~tken, Prof. Dr. K~ Z Bross, Dr. J. Schmid, Abteilung Haematologie und Onkologie, Med. Univ.-Klinik, A1bert-Ludwigs-Universit/it, Hugstetter Str. 55, W-7800 Freiburg; Dr. med. Eva Lang, Merrell Dow Pharma GmbH, W-6090 Riisselsheim, PD Dr. F. SOrgel, Institut for Biomed. u. Pharmaz. Forschung, W-8501 NiirnbergHeroldsberg, Germany.
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[7]. Unlike beta-lactams that show an affinity to enzymes, teicoplanin interacts with a structural component of the cell wall (i.e. the muramyl-pentapeptide's D-alanyl-Dalanine). Therefore, cross-resistances between beta-lactams and teicoplanin do not exist. Furthermore, one-step resistant mutations have not been found, as it seems to be unlikely that the structure of the muramyl-pentapeptide could be easily changed to inhibit teicoplanin binding [8]. Teicoplanin has been effectively used in combination with amikacin and ceftazidime in empiric antibiotic treatment of febrile episodes in neutropenic patients with acute leucaemia [9]; the substance is well tolerated when given intravenously [10]. The aim of this study was to evaluate prospectively the efficacy and tolerability of teicoplanin in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides. A preliminary analysis consisting of the first 11 patients treated has recently been reviewed [11]. Patients and Methods
Study Design: Patients undergoing an autologous or allogeneic bone marrow transplant were treated with whole-body irradiation and chemotherapy or chemotherapy alone. Consequently, leucocyte counts fell to a minimum starting approximately on day 4--6 following BMT. Antimicrobial therapy with a cephalosporin and an aminoglycoside was initiated when fever occurred. Teicoplanin was added 48 h later if the patient demonstrated an inadequate response to this regimen. If the fever did not diminish after two days with teicoplanin or reappeared within 48 h, amphotericin B was added. This therapeutic regimen was continued until the patient became afebrile and the leucocyte count reached a value of 1000/mm3. For evaluating the efficacy of this antimicrobial regimen, clinical outcome was defined as cure if the clinical signs and symptoms of the infection were completely eradicated without any evidence of infection or of recurrence at the termination of therapy. When clinical findings subsided during teicoplanin treatment but showed incomplete infection resolution, patients were judged to have clinically improved. Therapy failure was defined as no apparent response to therapy. Recurrence was defined as initial improvement of clinical findings with subsequent aggravation of the clinical condition caused by infection after treatment. If, in the investigator's opinion, for any reason the case was considered to be not evaluable, this was taken into consideration. Patient enrollment: Any hospitalized bone marrow transplant patient of either sex, 12 years and older, with suspected or established infection with gram-positive bacteria which did not respond primarily to beta-lactams and aminoglycosides was included in the clinical study after giving written informed consent. Patients were excluded for pregnancy or known allergy to vancomycin. The protocol of this study was approved by the ethics committee of the University of Freiburg, Germany. Patient data: According to the criteria stated above, 20 patients, nine male and 11 female, entered the study. The mean age was 30.6 + 8.9 years, ranging from 17 to 44 years. Body weight ranged from 42 to 99 kg with mean weight of 65.5 + 13.9 kg; mean height was 171.9 ___9.6 cm. The overall clinical condition was good in 12 patients, moderate in six, and life- threatening in two patients.
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Infections: All but three patients suffered from a septicaemia of unknown origin. In two patients the septicaemia was clearly related to a central venous and a portal catheter, respectively. The third patient had a urosepsis. Three patients suffered from additional infections, one being a severe acute urinary tract infection (UTI) caused by gram-negative bacteria; the second patient developed a moderate pyodermia; and the third patient developed a moderate intestinal torulopsis glabrata infection. Underlying diseases: Patients were transplanted for acute myeloid leucaemia (5 patients), acute lymphocytic leucaemia (1 patient), non- Hodgkin's lymphoma (5 patients), testicular carcinoma (3 patients), recurrence of Hodgkin's disease (3 patients) and one patient each with myelodysplasia (RAEB-T), chronic myeloid leucaemia and severe aplastic anaemia. Bone marrowtransplantation: Allogeneicbone marrow transplantations were performed in eight patients, autologous BMT in 12 patients. Predisposing and complicatingfactors: Six patients had a history of a previous hypersensitivity reaction to imipenem, penicillin, procarbazine, propyphenazon, metoclopramide, triflupromazine and flucloxacillin. Teicoplanin therapy: Teicoplanin was administered to all patients intravenously. Eighteen patients received 400 mg teicoplanin once daily with the exception of two. One patient received 200 rag/day for six days and then 400 mg/day for seven days. Initially, the remaining patient received 800 mg/day, then 200 mg/day for two days and 400 mg/day the subsequent days. The time period for teicoplanin ranged from four to 30 days, mean 14 days _+ eight days. Concomitant antimicrobial therapy: Concomitant antibiotic therapy, defined as treatment ending at the earliest three days after the initial teicoplanin, was given to 19 patients. All patients received the above- described therapy regimen (i.e. ceftazidime plus netilmicin plus teicoplanin) except for four patients who revealed allergies to cephalosporins; they received imipenem plus teicoplanin. One patient was treated with ceftriaxone instead of ceftazidime, another two patients received only a combination of netilmicin plus teicoplanin or ceftazidime plus teicoplanin, respectively. On one patient with a catheter-related septicaemia, teicoplanin was given as specific monotherapy, since a coagulasenegative staphylococcus had been isolated as the causative organism. Figure 1 shows the therapy regimen of each individual patient. Previous antimicrobial therapy: Previous antibiotic therapy, i.e. treatment that was initiated at least three days before teicoplanin was started and/or terminated at the end of the first day after onset, was given to seven patients. Ceftazidime and co-trimoxazole were administered three times, netilmicin was given twice, ceftriaxone and imipenem were given once. Selectiveintestinaldecontamination: Selective intestinal decontamination was performed in two patients prior to therapy (same definition as above), using oral paromomycine, teicoplanin, or ketoconazole. Concomitant selective intestinal decontamination was carried out in 19 patients who received ketoconazole, paromomycine, teicoplanin. Therapyassessement: Prior to treatment blood cultures were obtained for bacteriological evaluation. Routine laboratory testing was done as well as haematology and urine examination. During therapy haematological parameters including differential blood cell counts were assessed daily. Bacteriological cultureswere again taken during and after treatment. Routine laboratory screening was repeated two days later. Follow-up of pathological findings were evaluated until they returned to previous levels.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients
subsequent therapy
patients 1
--
2--
;:::
==================================
3-4--
I
I
I
I
9 10 11 12
15 16 17 18 19 20
antibiotics Figure 1: Antibiotics and dosages of antimicrobial therapy. Results
Clinical Outcome All 20 patients who had been studied according to the described protocol responded to therapy. Nineteen patients were clinically cured and one patient had improved at the termination of antibiotic treatment. All ten patients with moderate infections were cured; of the ten patients with severe infections, nine were cured and one patient showed clinical improvement. Since all patients except one received a BMT within 14 days before teicoplanin administration, special attention was paid to the leucocyte count in order to monitor haeInfection 19 (1991) No. 3
matological reconstitution. All patients treated were severely neutropenic when teicoplanin was started. Leucocyte counts of > 1000/mm 3were reached after a median of 20 days post BMT (13 days after onset of teicoplanin therapy). This occurred between day 11 and day 37 after BMT (day 0-31) after onset of teicoplanin) (Figure 2), except for one patient who entered the study 67 days post BMT with a leucocyte count of 6300/mm 3. Graft versus host disease, delayed take or graft failures were not observed in any patient under study.
Bacteriological Outcome As expected from previous experience, blood cultures
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Patients with leucocyte counts > 1000/mm3 (patients cumulated)
25
100%
~ = 11.30 +5.45
2O
80%
15
60% 40%
5
20%
without initial dose
0 0
10 20 30 Days after bone marrow transplantation
I
I
I
I
I
I
2
40
I
I
I
I
I
I
I
I
I
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I
I
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10
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26 days
Figure 3: Mean trough levels of teicoplanin serum concentration.
Figure 2: Time of reconstitution of leucocyte counts.
were non-diagnostic. The only causative gram-positive pathogen which could be isolated in two patients was a coagulase-negative staphylococcus. The agar diffusion test revealed that this staphylococcus was fully sensitive to teicoplanin. Three gram-negative organisms could be isolated, in one case Escherichia coli and in another case E. coli and Klebsiella spp. In all four cases where microorganisms had been identified previously (i.e. Klebsiella spp., E. coli, coagulasenegative staphylococcus), elimination of the causative organism was accomplished, suggesting that the pathogens
were absent after treatment. Bacteriological superinfections or colonization were not observed.
Teicoplanin Plasma Levels A total of 224 measurements of teicoplanin in plasma were performed in 16 patients. For each single patient the individual mean was calculated. The mean trough level for all patients, i.e. 24 h after injection, was 11.30 + 5.45 mg/l. Figure 3 demonstrates the time course of the mean trough levels during therapy.
/
cured
General condition
/
mild impairment
moderate impairment
severe
// 1 month before BMT
// Day 0
Day9
10
11
12
13
14
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Figure 4: Therapy course in a patient with septicaemia after bone marrow transplantation (BMT).
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A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients Safety
Laboratory Safety Data~Adverse Drug Reactions Laboratory parameters were frequently elevated in septicaemic patients. These consisted mostly of changes in liver enzymes/bilirubin (n = 10) or renal function impairment such as augmentation of urea (n = 8); such changes were related either to the underlying disease or the concomitant medication. Serum urea levels were already elevated before therapy and did not show any worsening throughout the study course. Furthermore, the serum creatinine levels did not increase during antibiotic therapy. During the observation period only one adverse drug reaction was observed, i.e. a mild allergic reaction under therapy with ceftazidime/netilmicin (i.v.) and paromomycin/ ketoconazole (orally) which subsided without therapeutic measures. Overall Assessment o f General and Local Tolerability General and local tolerability of teicoplanin was good in all 20 patients. In all cases the study could be terminated as planned. Overall clinical condition was good in 17 and moderate in three cases. In the case of the catheter-related septicaemia, it was necessary to remove the central venous catheter. Figure 4 shows the clinical course in one patient. Discussion
Teicoplanin is a new glycopeptide antibiotic with a wide range of indications [11-13]. It has been used successfully for the treatment of infections in immunocompromised and/or immunosuppressed patients, including septicaemia and catheter-related infections [9,14--16], either alone or in combination with cephalosporins and aminoglycosides. Considering our experience with an overall cure rate of more than 90% and the absence of adverse drug reactions References
i. Klastersky, J.: Concept of empiric therapy with antibiotic combinations. Indications and limits. Am. J. Med. 80 (Suppl. 5c) (1986) 2- 12. 2. Young, L. S.: Empirical antimicrobial therapy in the neutropenic host. N. EngL J. Med. 315 (1986) 580-581. 3. Meyers, J. D.: Infections in bone marrow transplant recipients. Am. J. Med. 81 (Suppl. la) (1986) 27-38.
in severely neutropenic patients, it seems that teicoplanin is a very effective and well tolerated antimicrobial substance when used to treat septicaemia in bone marrow transplant patients demonstrating inadequate primary response to beta-lactam and aminoglycoside therapy. The observed haematological reconstitution time for leucocytes (median 20 days after BMT) c o m p a r e d with B M T patients who did not receive this antimicrobial therapy [17-20] revealed no difference with respect to the time of haematopoietic constitution, indicating that the antimicrobial therapy regimen under study did not prolong neutropenia. Furthermore, we did not observe any ototoxicity or nephrotoxicity during the course of antibiotic therapy, although most patients received potentially ototoxic drugs together with teicoplanin. This suggests that teicoplanin does not increase the riskoftoxicityin aminoglycoside-treatedpatients. In addition to the positive ratio of efficacy to safety, the study indicates that the time and cost savings of one dose of teicoplanin per day reveals an advantage for patients, nurses and physicians. Although open studies on antibiotics should be evaluated with precaution, teicoplanin seems to be an alternative to the standard therapy of septicaemia during bone marrow transplantation. Further investigations with a larger number of patients are presently under way in order to gain additional experience with regard to this antimicrobial therapeutic regimen and to generate additional data to substantiate our previous findings. Acknowledgements
We thank the nursing and medical staff of the Bone Marrow Transplant Unit for their cooperation. We also thank Berthold Schaaf, factum GmbH, Offenbach, Germany, for the data analysis. 8. Thabaut, A., Meyran, M.: Comparative in vitro study of the activityof teichomycin, vancomycin,and N-formimidoyl-thienamycinon Staphylococcus aureus. Chemioterapia 2 (Suppl. 5) (1983) 12-13. 9. Del Favero, A., Menichetti, F., Guerciolini, R., Bucaneve, G., Baldelli, F., Aversa, F., Terenzi, A., Davis, S., Pauluzzi, S.: Prospective ran-
4. Pallanza, R., Berti, M., Goldstein, B. P., Mapelli, E., Randisi, E., Scotti, R., Arioli, V.: Teichomycin, in vitro and in vivo evaluation in
10.
comparison with other antibiotics. J. Antimicrob. Chemother. 11 (1983) 419-425. 5. Traina, G. L., Bonati, M.: Pharmacokinetics of teicoplanin in man after intravenous administration. J. Pharmacokinet. Biopharm. 12 (1984) 119- 128.
11.
6. Verbist, L., Tjandramaga, B., Hendrickx, B., Van Hecken, A., Van Melle, B., Verbeseit, 1L, Verhaegen, J., De Schepper, P. J.: In vitro ac-
12.
tivity and human pharmacokinetics of teicoplanin. Antimicrob. Agents Chemother. 26 (1984) 881-886. 7. Somma,S., Gastaido, L.: Mechanismsof action of teichomycinA2, a new antibiotic. In: Periti, P., Gialdroni-Grassi, G. (eds.): Curr. Chemother, and Immunother., Bd. I, Proc. 12th Int. Cong. Chemother., Florence, 19-24.07.1981; American Society for Microbiology, Washington 1982, p. 343-345.
13.
14.
domized trial of teicoplanin for empiric combined antibiotic therapy in febrile, granulocytopenic acute leukemia patients. Antimicrob. Agents Chemother. 31 (1987) 1126-1129. Stille, W., Sietzen, W., Dieterich, It.-A., Fell, J. J.: Clinical efficacyof teicoplanin. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 69-79. Lang, E., Schmidt, J., Fauser, A. A.: A clinical trial on efficacy and safety of teicoplanin in combination with beta-lactams and aminoglycosides in the treatment of serve sepsis of patients undergoing allogeneic/autologous bone marrow transplantation. Br. J. Haematol. 76 (Suppl, 2) (1990). Greenwood, D.- Microbiological properties of teicoplanin. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 1-13. Del Bene, V. E., John, J. F. jr., Twitty,J. A., Lewis,J. W.: Anti-staphylococcal activityof teicoplanin, vancomycin,and other antimicrobial agents: The significance of methicillin resistance. J. Infect. Dis. 154 (1986) 349-352. Verhagen, C., De Pauw, B. E.: Teicoplanin for therapy of gram-positive infections in neutropenic patients. Int. J. Clin. Pharmacol. Res. 7 (1987) 491-498.
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A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients 15. Webster, A., Russell, S. J., Souhami, R, L., Richards, J. D. M., Goldstone, A. H., Gruneberg, R. N.: Use of teicoplanin for Hickman catheter associated staphylococcal infection in immunosuppressed patients. J. Hosp. Infect. 10 (1987) 77--82. 16. Lemerle, S., de La Rocque, F., Lamy, R., Fremaux, A., Bernaudin, F , Lobut, J.-B., Reinert, P.: Teicoptanin in combination therapy for febrile episodes in neutropenic and non-neutropenic paediatric patients. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 113-116. 17. Burnett, A. K., Tansey, P., Hills, C., Alcorn, M. J., Sbeehan, T., McDonald, G. A., Banham, S. W.: Haematological reconstitution following high dose and supralethal chemo-radiotherapy using stored, non-cryopreserved autologous bone marrow. Br. J. Haemotol. 54 (1983) 309-316.
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18. Harada, M., Yoshida, T., Ishino, C., Matsue, K., Kodo, H., Mori, T., Shiobara, S., Odaka, K., Ohtake, S., Kondo, K., Nakao, S., Ueda, M., Hattory, K.-I., and the Kanazawa University Bone Marrow Transplant Team: Haematologic recovery followingautologous and allogeneic bone marrow transplantation. Exp. Haematol. 11 (1983) 841848.
19. Stewart, F. M., Kaiser, D. L, Ishitani, K., Pirsch, G., Niskanen, E.: Progenitor cell numbers (CFU-GM, CFU-D, and CFU-Mix) and haematopoietic recovery following autologous marrow transplantation. Exp. Hematol. 17 (1989) 974-980.
20. Keever, C. A., Small, T., FIomenberg, N., Heller, G., Pekle, K., Black, P., Pecora, A., Gillio, A., Kernan, N., O'Reiily, R. J.: Immune reconstitution followingbone marrow transplantation: Comparison of recipients of conventional marrow grafts. Blood 73 (1989) 1340-1350.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Mtinchen, Miinchen 199t
A. A. Fauser, E. Lang, G. D61ken, K. J. Bross, J. Schmid, F. S6rgel
Treatment of Severe Sepsis in Bone Marrow Transplant Recipients with Teicoplanin in Combination with [5-Lactams and Aminoglycosides Summary: We evaluated teicoplanin for suspected gram-positive infections after inadequate response to initial empiric beta-lactam and aminoglycoside combination therapy. All 20 patients included in this study received either an allogeneic (8 patients) or an autologous (12 patients) bone marrow transplant for acute myeloid leucaemia (AML), non-Hodgkin's-lymphoma (NHL, high grade) or other malignant diseases. All patients developing primary septicaemia of unknown origin (18 patients) or catheter-related septicaemia (2 patients) were treated with 400 mg teicoplanin, administered i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g i.v., t.i.d.;
netilmicin 400 mg once daily). All patients responded to therapy, 19 patients were clinically cured and one patient improved under therapy. The therapeutic regimen was well tolerated; only one adverse drug reaction was observed. We did not observe any delayed take or prolonged neutropenia or thrombocytopenia with this therapeutic regimen when our patients were compared to other bone marrow transplant patients (who did not receive this antimicrobiat therapy). Our results suggest that teicoplanin is a potentially effective and well tolerated antimicrobial agent in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides.
Zusammenfassung: Teicoplanin in Kombination mit ~-Laktamen und Aminoglykosiden bei Knochenmarktransplantatempffdngern mit schwerer Sepsis. Wir unter-
on mit einem Cephalosporin und einem Aminoglykosid (Ceftazidim 2 g i.v., 3 x/die, Netilmicin 400 mg, 1 x/die). Alle behandelten Patienten sprachen auf diese Therapie an. 19 Patienten wurden klinisch geheilt, ein Patient besserte sich unter dieser Therapie. Die Kombinationstherapie wurde gut vertragen, unerwiinschte Arzneimittelwirkungen traten w/ihrend der Studie nicht auf. Wir beobachteten kein verz6gertes Angehen des Knochenmarks oder eine Verl/ingerung der Thrombozytopenie unter dieser Behandlung im Vergleich zu anderen knochenmarktransplantierten Patienten, die diese antimikrobielle Behandlung nicht erhielten. Unsere Ergebnisse zeigen, dab Teicoplanin ein wirksames und gut Vertr/igliches Antibiotikum fiir knochenmarktransplantierte Patienten ist, die prim~ir nicht auf die Kombinationstherapie mit [~-Laktam-Antibiotika und Aminoglykosiden ansprechen.
suchten Teicoplanin bei vermuteten grampositiven Infektionen nach ungeniigendem Ansprechen auf die anf/ingliche Kombinationstherapie von ~-Laktam-Antibiotika und Aminoglykosiden. Alle 20 in dieser Studie erfaBten Patienten wurden entweder allogen (8 Patienten) oder autolog (12 Patienten) transplantiert mit folgenden Grundkrankheiten: akute myeloische Leuk/imie (AML), Non-Hodgldn-Lymphom (NHL) oder andere maligne Erkrankungen. Alle Patienten, die eine prim~ire Septik/imie unbekannten Ursprungs entwickelten (18 Patienten) oder unter einer Katheter-bedingten Septik~imie (2 Patienten) litten, wurden mit 400 mg Teicoplanin behandelt. Die Verabreichung von Teicoplanin erfolgte einmal t/iglich intraven6s in Kombinati-
Introduction Granulocytopenic patients, especially those receiving a bone marrow transplant, present special therapeutic problems, since infections with gram- positive microorganisms are an increasing cause of morbidity and mortality [1, 2]. Patients receiving a bone marrow transplant (BMT) are exposed to long-term use o f central venous catheters, which is considered to be one of the factors responsible for the increased infection rate; additional factors include existing neutropenia with granulocyte counts below 100/mm3 and the inflammation of mucous membranes, which lowers local defense mechanisms [3]. Numerous efforts have been made to decrease the incidence of febrile episodes in patients following BMT. Since many causative gram-positive microorganisms show resistance to beta-lactams and aminoglycosides, it seems resonable to include a highly ac-
tive anti-gram-positive agent such as teicoplanin in the standard antimicrobial regimen. Teicoplanin is a new glycopeptide antibiotic active against gram-positive microorganisms, e.g. staphylococci including strains resistant to methicillin, streptococci including enterococci and pneumococci, corynebacteria group J K , and anaerobic organisms including Clostridium difficile [4]. The pharmacokinetics of teicoplanin permit a once-daily administration either intravenously, as bolus or infusion, or intramuscularly [5, 6]. It is bactericidal through inhibition of the peptidoglycane-elongation in the bacterial cell wall Prof. Dr. A. A. Fauser, Prof. Dr. G. Di~tken, Prof. Dr. K~ Z Bross, Dr. J. Schmid, Abteilung Haematologie und Onkologie, Med. Univ.-Klinik, A1bert-Ludwigs-Universit/it, Hugstetter Str. 55, W-7800 Freiburg; Dr. med. Eva Lang, Merrell Dow Pharma GmbH, W-6090 Riisselsheim, PD Dr. F. SOrgel, Institut for Biomed. u. Pharmaz. Forschung, W-8501 NiirnbergHeroldsberg, Germany.
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A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients
[7]. Unlike beta-lactams that show an affinity to enzymes, teicoplanin interacts with a structural component of the cell wall (i.e. the muramyl-pentapeptide's D-alanyl-Dalanine). Therefore, cross-resistances between beta-lactams and teicoplanin do not exist. Furthermore, one-step resistant mutations have not been found, as it seems to be unlikely that the structure of the muramyl-pentapeptide could be easily changed to inhibit teicoplanin binding [8]. Teicoplanin has been effectively used in combination with amikacin and ceftazidime in empiric antibiotic treatment of febrile episodes in neutropenic patients with acute leucaemia [9]; the substance is well tolerated when given intravenously [10]. The aim of this study was to evaluate prospectively the efficacy and tolerability of teicoplanin in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides. A preliminary analysis consisting of the first 11 patients treated has recently been reviewed [11]. Patients and Methods
Study Design: Patients undergoing an autologous or allogeneic bone marrow transplant were treated with whole-body irradiation and chemotherapy or chemotherapy alone. Consequently, leucocyte counts fell to a minimum starting approximately on day 4--6 following BMT. Antimicrobial therapy with a cephalosporin and an aminoglycoside was initiated when fever occurred. Teicoplanin was added 48 h later if the patient demonstrated an inadequate response to this regimen. If the fever did not diminish after two days with teicoplanin or reappeared within 48 h, amphotericin B was added. This therapeutic regimen was continued until the patient became afebrile and the leucocyte count reached a value of 1000/mm3. For evaluating the efficacy of this antimicrobial regimen, clinical outcome was defined as cure if the clinical signs and symptoms of the infection were completely eradicated without any evidence of infection or of recurrence at the termination of therapy. When clinical findings subsided during teicoplanin treatment but showed incomplete infection resolution, patients were judged to have clinically improved. Therapy failure was defined as no apparent response to therapy. Recurrence was defined as initial improvement of clinical findings with subsequent aggravation of the clinical condition caused by infection after treatment. If, in the investigator's opinion, for any reason the case was considered to be not evaluable, this was taken into consideration. Patient enrollment: Any hospitalized bone marrow transplant patient of either sex, 12 years and older, with suspected or established infection with gram-positive bacteria which did not respond primarily to beta-lactams and aminoglycosides was included in the clinical study after giving written informed consent. Patients were excluded for pregnancy or known allergy to vancomycin. The protocol of this study was approved by the ethics committee of the University of Freiburg, Germany. Patient data: According to the criteria stated above, 20 patients, nine male and 11 female, entered the study. The mean age was 30.6 + 8.9 years, ranging from 17 to 44 years. Body weight ranged from 42 to 99 kg with mean weight of 65.5 + 13.9 kg; mean height was 171.9 ___9.6 cm. The overall clinical condition was good in 12 patients, moderate in six, and life- threatening in two patients.
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Infections: All but three patients suffered from a septicaemia of unknown origin. In two patients the septicaemia was clearly related to a central venous and a portal catheter, respectively. The third patient had a urosepsis. Three patients suffered from additional infections, one being a severe acute urinary tract infection (UTI) caused by gram-negative bacteria; the second patient developed a moderate pyodermia; and the third patient developed a moderate intestinal torulopsis glabrata infection. Underlying diseases: Patients were transplanted for acute myeloid leucaemia (5 patients), acute lymphocytic leucaemia (1 patient), non- Hodgkin's lymphoma (5 patients), testicular carcinoma (3 patients), recurrence of Hodgkin's disease (3 patients) and one patient each with myelodysplasia (RAEB-T), chronic myeloid leucaemia and severe aplastic anaemia. Bone marrowtransplantation: Allogeneicbone marrow transplantations were performed in eight patients, autologous BMT in 12 patients. Predisposing and complicatingfactors: Six patients had a history of a previous hypersensitivity reaction to imipenem, penicillin, procarbazine, propyphenazon, metoclopramide, triflupromazine and flucloxacillin. Teicoplanin therapy: Teicoplanin was administered to all patients intravenously. Eighteen patients received 400 mg teicoplanin once daily with the exception of two. One patient received 200 rag/day for six days and then 400 mg/day for seven days. Initially, the remaining patient received 800 mg/day, then 200 mg/day for two days and 400 mg/day the subsequent days. The time period for teicoplanin ranged from four to 30 days, mean 14 days _+ eight days. Concomitant antimicrobial therapy: Concomitant antibiotic therapy, defined as treatment ending at the earliest three days after the initial teicoplanin, was given to 19 patients. All patients received the above- described therapy regimen (i.e. ceftazidime plus netilmicin plus teicoplanin) except for four patients who revealed allergies to cephalosporins; they received imipenem plus teicoplanin. One patient was treated with ceftriaxone instead of ceftazidime, another two patients received only a combination of netilmicin plus teicoplanin or ceftazidime plus teicoplanin, respectively. On one patient with a catheter-related septicaemia, teicoplanin was given as specific monotherapy, since a coagulasenegative staphylococcus had been isolated as the causative organism. Figure 1 shows the therapy regimen of each individual patient. Previous antimicrobial therapy: Previous antibiotic therapy, i.e. treatment that was initiated at least three days before teicoplanin was started and/or terminated at the end of the first day after onset, was given to seven patients. Ceftazidime and co-trimoxazole were administered three times, netilmicin was given twice, ceftriaxone and imipenem were given once. Selectiveintestinaldecontamination: Selective intestinal decontamination was performed in two patients prior to therapy (same definition as above), using oral paromomycine, teicoplanin, or ketoconazole. Concomitant selective intestinal decontamination was carried out in 19 patients who received ketoconazole, paromomycine, teicoplanin. Therapyassessement: Prior to treatment blood cultures were obtained for bacteriological evaluation. Routine laboratory testing was done as well as haematology and urine examination. During therapy haematological parameters including differential blood cell counts were assessed daily. Bacteriological cultureswere again taken during and after treatment. Routine laboratory screening was repeated two days later. Follow-up of pathological findings were evaluated until they returned to previous levels.
Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients
subsequent therapy
patients 1
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3-4--
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9 10 11 12
15 16 17 18 19 20
antibiotics Figure 1: Antibiotics and dosages of antimicrobial therapy. Results
Clinical Outcome All 20 patients who had been studied according to the described protocol responded to therapy. Nineteen patients were clinically cured and one patient had improved at the termination of antibiotic treatment. All ten patients with moderate infections were cured; of the ten patients with severe infections, nine were cured and one patient showed clinical improvement. Since all patients except one received a BMT within 14 days before teicoplanin administration, special attention was paid to the leucocyte count in order to monitor haeInfection 19 (1991) No. 3
matological reconstitution. All patients treated were severely neutropenic when teicoplanin was started. Leucocyte counts of > 1000/mm 3were reached after a median of 20 days post BMT (13 days after onset of teicoplanin therapy). This occurred between day 11 and day 37 after BMT (day 0-31) after onset of teicoplanin) (Figure 2), except for one patient who entered the study 67 days post BMT with a leucocyte count of 6300/mm 3. Graft versus host disease, delayed take or graft failures were not observed in any patient under study.
Bacteriological Outcome As expected from previous experience, blood cultures
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A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients
Patients with leucocyte counts > 1000/mm3 (patients cumulated)
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Figure 3: Mean trough levels of teicoplanin serum concentration.
Figure 2: Time of reconstitution of leucocyte counts.
were non-diagnostic. The only causative gram-positive pathogen which could be isolated in two patients was a coagulase-negative staphylococcus. The agar diffusion test revealed that this staphylococcus was fully sensitive to teicoplanin. Three gram-negative organisms could be isolated, in one case Escherichia coli and in another case E. coli and Klebsiella spp. In all four cases where microorganisms had been identified previously (i.e. Klebsiella spp., E. coli, coagulasenegative staphylococcus), elimination of the causative organism was accomplished, suggesting that the pathogens
were absent after treatment. Bacteriological superinfections or colonization were not observed.
Teicoplanin Plasma Levels A total of 224 measurements of teicoplanin in plasma were performed in 16 patients. For each single patient the individual mean was calculated. The mean trough level for all patients, i.e. 24 h after injection, was 11.30 + 5.45 mg/l. Figure 3 demonstrates the time course of the mean trough levels during therapy.
/
cured
General condition
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mild impairment
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// 1 month before BMT
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Figure 4: Therapy course in a patient with septicaemia after bone marrow transplantation (BMT).
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Infection 19 (1991) No. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1991
A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients Safety
Laboratory Safety Data~Adverse Drug Reactions Laboratory parameters were frequently elevated in septicaemic patients. These consisted mostly of changes in liver enzymes/bilirubin (n = 10) or renal function impairment such as augmentation of urea (n = 8); such changes were related either to the underlying disease or the concomitant medication. Serum urea levels were already elevated before therapy and did not show any worsening throughout the study course. Furthermore, the serum creatinine levels did not increase during antibiotic therapy. During the observation period only one adverse drug reaction was observed, i.e. a mild allergic reaction under therapy with ceftazidime/netilmicin (i.v.) and paromomycin/ ketoconazole (orally) which subsided without therapeutic measures. Overall Assessment o f General and Local Tolerability General and local tolerability of teicoplanin was good in all 20 patients. In all cases the study could be terminated as planned. Overall clinical condition was good in 17 and moderate in three cases. In the case of the catheter-related septicaemia, it was necessary to remove the central venous catheter. Figure 4 shows the clinical course in one patient. Discussion
Teicoplanin is a new glycopeptide antibiotic with a wide range of indications [11-13]. It has been used successfully for the treatment of infections in immunocompromised and/or immunosuppressed patients, including septicaemia and catheter-related infections [9,14--16], either alone or in combination with cephalosporins and aminoglycosides. Considering our experience with an overall cure rate of more than 90% and the absence of adverse drug reactions References
i. Klastersky, J.: Concept of empiric therapy with antibiotic combinations. Indications and limits. Am. J. Med. 80 (Suppl. 5c) (1986) 2- 12. 2. Young, L. S.: Empirical antimicrobial therapy in the neutropenic host. N. EngL J. Med. 315 (1986) 580-581. 3. Meyers, J. D.: Infections in bone marrow transplant recipients. Am. J. Med. 81 (Suppl. la) (1986) 27-38.
in severely neutropenic patients, it seems that teicoplanin is a very effective and well tolerated antimicrobial substance when used to treat septicaemia in bone marrow transplant patients demonstrating inadequate primary response to beta-lactam and aminoglycoside therapy. The observed haematological reconstitution time for leucocytes (median 20 days after BMT) c o m p a r e d with B M T patients who did not receive this antimicrobial therapy [17-20] revealed no difference with respect to the time of haematopoietic constitution, indicating that the antimicrobial therapy regimen under study did not prolong neutropenia. Furthermore, we did not observe any ototoxicity or nephrotoxicity during the course of antibiotic therapy, although most patients received potentially ototoxic drugs together with teicoplanin. This suggests that teicoplanin does not increase the riskoftoxicityin aminoglycoside-treatedpatients. In addition to the positive ratio of efficacy to safety, the study indicates that the time and cost savings of one dose of teicoplanin per day reveals an advantage for patients, nurses and physicians. Although open studies on antibiotics should be evaluated with precaution, teicoplanin seems to be an alternative to the standard therapy of septicaemia during bone marrow transplantation. Further investigations with a larger number of patients are presently under way in order to gain additional experience with regard to this antimicrobial therapeutic regimen and to generate additional data to substantiate our previous findings. Acknowledgements
We thank the nursing and medical staff of the Bone Marrow Transplant Unit for their cooperation. We also thank Berthold Schaaf, factum GmbH, Offenbach, Germany, for the data analysis. 8. Thabaut, A., Meyran, M.: Comparative in vitro study of the activityof teichomycin, vancomycin,and N-formimidoyl-thienamycinon Staphylococcus aureus. Chemioterapia 2 (Suppl. 5) (1983) 12-13. 9. Del Favero, A., Menichetti, F., Guerciolini, R., Bucaneve, G., Baldelli, F., Aversa, F., Terenzi, A., Davis, S., Pauluzzi, S.: Prospective ran-
4. Pallanza, R., Berti, M., Goldstein, B. P., Mapelli, E., Randisi, E., Scotti, R., Arioli, V.: Teichomycin, in vitro and in vivo evaluation in
10.
comparison with other antibiotics. J. Antimicrob. Chemother. 11 (1983) 419-425. 5. Traina, G. L., Bonati, M.: Pharmacokinetics of teicoplanin in man after intravenous administration. J. Pharmacokinet. Biopharm. 12 (1984) 119- 128.
11.
6. Verbist, L., Tjandramaga, B., Hendrickx, B., Van Hecken, A., Van Melle, B., Verbeseit, 1L, Verhaegen, J., De Schepper, P. J.: In vitro ac-
12.
tivity and human pharmacokinetics of teicoplanin. Antimicrob. Agents Chemother. 26 (1984) 881-886. 7. Somma,S., Gastaido, L.: Mechanismsof action of teichomycinA2, a new antibiotic. In: Periti, P., Gialdroni-Grassi, G. (eds.): Curr. Chemother, and Immunother., Bd. I, Proc. 12th Int. Cong. Chemother., Florence, 19-24.07.1981; American Society for Microbiology, Washington 1982, p. 343-345.
13.
14.
domized trial of teicoplanin for empiric combined antibiotic therapy in febrile, granulocytopenic acute leukemia patients. Antimicrob. Agents Chemother. 31 (1987) 1126-1129. Stille, W., Sietzen, W., Dieterich, It.-A., Fell, J. J.: Clinical efficacyof teicoplanin. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 69-79. Lang, E., Schmidt, J., Fauser, A. A.: A clinical trial on efficacy and safety of teicoplanin in combination with beta-lactams and aminoglycosides in the treatment of serve sepsis of patients undergoing allogeneic/autologous bone marrow transplantation. Br. J. Haematol. 76 (Suppl, 2) (1990). Greenwood, D.- Microbiological properties of teicoplanin. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 1-13. Del Bene, V. E., John, J. F. jr., Twitty,J. A., Lewis,J. W.: Anti-staphylococcal activityof teicoplanin, vancomycin,and other antimicrobial agents: The significance of methicillin resistance. J. Infect. Dis. 154 (1986) 349-352. Verhagen, C., De Pauw, B. E.: Teicoplanin for therapy of gram-positive infections in neutropenic patients. Int. J. Clin. Pharmacol. Res. 7 (1987) 491-498.
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A. A. Fauser et al.: Teicoplanin in Bone Marrow Transplant Recipients 15. Webster, A., Russell, S. J., Souhami, R, L., Richards, J. D. M., Goldstone, A. H., Gruneberg, R. N.: Use of teicoplanin for Hickman catheter associated staphylococcal infection in immunosuppressed patients. J. Hosp. Infect. 10 (1987) 77--82. 16. Lemerle, S., de La Rocque, F., Lamy, R., Fremaux, A., Bernaudin, F , Lobut, J.-B., Reinert, P.: Teicoptanin in combination therapy for febrile episodes in neutropenic and non-neutropenic paediatric patients. J. Antimicrob. Chemother. 21 (Suppl. A) (1988) 113-116. 17. Burnett, A. K., Tansey, P., Hills, C., Alcorn, M. J., Sbeehan, T., McDonald, G. A., Banham, S. W.: Haematological reconstitution following high dose and supralethal chemo-radiotherapy using stored, non-cryopreserved autologous bone marrow. Br. J. Haemotol. 54 (1983) 309-316.
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18. Harada, M., Yoshida, T., Ishino, C., Matsue, K., Kodo, H., Mori, T., Shiobara, S., Odaka, K., Ohtake, S., Kondo, K., Nakao, S., Ueda, M., Hattory, K.-I., and the Kanazawa University Bone Marrow Transplant Team: Haematologic recovery followingautologous and allogeneic bone marrow transplantation. Exp. Haematol. 11 (1983) 841848.
19. Stewart, F. M., Kaiser, D. L, Ishitani, K., Pirsch, G., Niskanen, E.: Progenitor cell numbers (CFU-GM, CFU-D, and CFU-Mix) and haematopoietic recovery following autologous marrow transplantation. Exp. Hematol. 17 (1989) 974-980.
20. Keever, C. A., Small, T., FIomenberg, N., Heller, G., Pekle, K., Black, P., Pecora, A., Gillio, A., Kernan, N., O'Reiily, R. J.: Immune reconstitution followingbone marrow transplantation: Comparison of recipients of conventional marrow grafts. Blood 73 (1989) 1340-1350.
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