Correwondence
INFECTIOUS INTERLEUKIN
COMPLICATIONS 2 THERAPY
OF
TO THE EDITOR
There has been concern about the number and the severity of the toxicities associatedwith the administration of interleukin 2 (IL 2). Particular attention has been focused on the capillary leak syndrome and the renal, neurological, and cardiovascular complications. The side effects are however very scheduledependant and when moderate doses of IL 2 are given as a continuous intravenous infusion without LAK cells, the toxicities are not severe and can be readily managed on an open ward.’ Infectious complications are rarely discussedin detail and are not mentioned at all in some reviews’,’ despite a reported incidence of up to 40%.3-6These studies have mainly focused on gram-positive infections associated with central venous lines and this has led to the recommendation that prophylactic antibiotics such as oral cephalosporins or penicillins should be used.3.5.6In trials with Eurocetus IL 2, the administration of prophylactic broad spectrum antibiotics is recommended. However, this is not an absolute requirement for entry into these studies and some participants do not adhere to this policy. In our experience, sepsiswith a wider range of organisms is a significant problem and current recommendations for prophylaxis need revision. We have treated 10 patients for renal cell carcinoma with 2 1 coursesof IL 2 at 3 x 1O6Cetus units per day by continuous intravenous infusion days 1 to 5 and 8 to 12, the cycle being repeated after 3 weeks. Responding patients received four further 5-day courses at 3-week intervals. Positive bacterial cultures were obtained in 8/10 patients (13/21 courses, 62%). Seven out of 13 infections (54%) were with gram-negative organisms (4 with “coliform” bacteria, 2 with Pseudomonas aeruginosa, 1 with Enterobacter sp.) and 6113 (46%) were with gram-positive bacteria (5 with Staphylococcus epidermidis, 1 with Bacillus sp.). Sites of infection included the tip or skin-entry site of the central venous catheter (5 and 3 episodes, respectively), the urine (2 episodes), and the blood (3 episodes). A clinical diagnosis of septicemia was made in another patient with disseminated intravascular coagulation, although blood cultures were negative. Flucloxacillin was administered with the last 5 coursesof IL 2 in this series of patients following publication of data suggesting that prophylaxis aimed at gram-positive organisms reduced the rate of infection.5 Despite this, three episodes of culture-positive infection from the tip of the central venous
CYTOKINE,
Vol. 2, No.
4 (July),
1990:
p 3 11
catheters occurred, 2/3 of the organisms isolated being gramnegative (“coliform” and Pseudomonas aeruginosa). In conclusion, culture-positive infections occur more frequently than previously reported and over half of these infections are due to gram-negative bacteria. Antibiotic prophylaxis is indicated in patients undergoing treatment with IL 2 but should cover gram-negative as well as gram-positive organisms. We now routinely use ciprofloxacin 250 mg bd orally as prophylaxis during IL 2 therapy. In addition, regular cultures of blood, urine, and central line entry sites must be taken during treatment and physicians should have a low threshold for starting or changing a patient’s anti-microbial cover. REFERENCE 1. Hamblin IJ (1990) Interleukin 2: side effects are acceptable. Br Med J 300:275-276. 2. Parkinson DR (1988) Interleukin 2 in cancer therapy. Semin One01 15:10-26. 3. Marolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher RI, Weiss GR, Doroshow JH, Jaffe HS, Roper M, Parkinson DR, Wiernik PH, Creekmore SP, Boldt DH (1989) Interleukin-2 and lymphokineactivated killer cell therapy of solid turnours: analysis of toxicity and management guidelines. .I Clin Oncol7:486-498. 4. Dutcher JP, Creekmore S, Weiss GR, Marolin K, Markowitz AB, Roper M, Parkinson D, Ciobanu N, Fisher RI, Boldt DH, Doroshow JH, Rayner AA, Hawkins M, Atkins M (1989) A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol7:477-485. 5. Hartmann LC, Urba WJ, Steis RG, Smith JW, Vander Molen LA, Creekmore SP, Sznol M, Casciano MA, Engler N, Longo DL (1989) Use of prophylactic antibiotics for prevention of intravascular catheter-related infections in interleukin-2 treated patients. J Nat Cancer Inst 81:90-93. 6. Bock SN, Lee RE, Fisher B, Robin JT, Schwartzentruber DJ, Wei JP, Callender DPE, Yang JC, Lotze MT, Pizza PA, Rosenberg SA (1990) A prospective randomised trial evaluating prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy. J Clin Oncol8:161-169.
J.R. Hardy J. Moore A. Lorentzos E. Ellis B. Jameson M.E. Gore Biological Therapies Unit Department of Medicine Royal Marsden Hospital Fulham Road, London SW3 6JJ, UK
311
INFECTIOUS INTERLEUKIN
COMPLICATIONS 2 THERAPY
OF
TO THE EDITOR
There has been concern about the number and the severity of the toxicities associatedwith the administration of interleukin 2 (IL 2). Particular attention has been focused on the capillary leak syndrome and the renal, neurological, and cardiovascular complications. The side effects are however very scheduledependant and when moderate doses of IL 2 are given as a continuous intravenous infusion without LAK cells, the toxicities are not severe and can be readily managed on an open ward.’ Infectious complications are rarely discussedin detail and are not mentioned at all in some reviews’,’ despite a reported incidence of up to 40%.3-6These studies have mainly focused on gram-positive infections associated with central venous lines and this has led to the recommendation that prophylactic antibiotics such as oral cephalosporins or penicillins should be used.3.5.6In trials with Eurocetus IL 2, the administration of prophylactic broad spectrum antibiotics is recommended. However, this is not an absolute requirement for entry into these studies and some participants do not adhere to this policy. In our experience, sepsiswith a wider range of organisms is a significant problem and current recommendations for prophylaxis need revision. We have treated 10 patients for renal cell carcinoma with 2 1 coursesof IL 2 at 3 x 1O6Cetus units per day by continuous intravenous infusion days 1 to 5 and 8 to 12, the cycle being repeated after 3 weeks. Responding patients received four further 5-day courses at 3-week intervals. Positive bacterial cultures were obtained in 8/10 patients (13/21 courses, 62%). Seven out of 13 infections (54%) were with gram-negative organisms (4 with “coliform” bacteria, 2 with Pseudomonas aeruginosa, 1 with Enterobacter sp.) and 6113 (46%) were with gram-positive bacteria (5 with Staphylococcus epidermidis, 1 with Bacillus sp.). Sites of infection included the tip or skin-entry site of the central venous catheter (5 and 3 episodes, respectively), the urine (2 episodes), and the blood (3 episodes). A clinical diagnosis of septicemia was made in another patient with disseminated intravascular coagulation, although blood cultures were negative. Flucloxacillin was administered with the last 5 coursesof IL 2 in this series of patients following publication of data suggesting that prophylaxis aimed at gram-positive organisms reduced the rate of infection.5 Despite this, three episodes of culture-positive infection from the tip of the central venous
CYTOKINE,
Vol. 2, No.
4 (July),
1990:
p 3 11
catheters occurred, 2/3 of the organisms isolated being gramnegative (“coliform” and Pseudomonas aeruginosa). In conclusion, culture-positive infections occur more frequently than previously reported and over half of these infections are due to gram-negative bacteria. Antibiotic prophylaxis is indicated in patients undergoing treatment with IL 2 but should cover gram-negative as well as gram-positive organisms. We now routinely use ciprofloxacin 250 mg bd orally as prophylaxis during IL 2 therapy. In addition, regular cultures of blood, urine, and central line entry sites must be taken during treatment and physicians should have a low threshold for starting or changing a patient’s anti-microbial cover. REFERENCE 1. Hamblin IJ (1990) Interleukin 2: side effects are acceptable. Br Med J 300:275-276. 2. Parkinson DR (1988) Interleukin 2 in cancer therapy. Semin One01 15:10-26. 3. Marolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher RI, Weiss GR, Doroshow JH, Jaffe HS, Roper M, Parkinson DR, Wiernik PH, Creekmore SP, Boldt DH (1989) Interleukin-2 and lymphokineactivated killer cell therapy of solid turnours: analysis of toxicity and management guidelines. .I Clin Oncol7:486-498. 4. Dutcher JP, Creekmore S, Weiss GR, Marolin K, Markowitz AB, Roper M, Parkinson D, Ciobanu N, Fisher RI, Boldt DH, Doroshow JH, Rayner AA, Hawkins M, Atkins M (1989) A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol7:477-485. 5. Hartmann LC, Urba WJ, Steis RG, Smith JW, Vander Molen LA, Creekmore SP, Sznol M, Casciano MA, Engler N, Longo DL (1989) Use of prophylactic antibiotics for prevention of intravascular catheter-related infections in interleukin-2 treated patients. J Nat Cancer Inst 81:90-93. 6. Bock SN, Lee RE, Fisher B, Robin JT, Schwartzentruber DJ, Wei JP, Callender DPE, Yang JC, Lotze MT, Pizza PA, Rosenberg SA (1990) A prospective randomised trial evaluating prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy. J Clin Oncol8:161-169.
J.R. Hardy J. Moore A. Lorentzos E. Ellis B. Jameson M.E. Gore Biological Therapies Unit Department of Medicine Royal Marsden Hospital Fulham Road, London SW3 6JJ, UK
311
