ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1992, p. 801-807 0066-4804/92/040801-07$02.00/0
Vol. 36, No. 4
Imipenem versus Gentamicin Combined with Either Cefuroxime or Cephalothin as Initial Therapy for Febrile Neutropenic Patients CORNELISSEN,l1* A.
GRAEFF,2 L. F. VERDONCK,1 T. BRANGER,3 M. ROZENBERG-ARSKA,4 J. VERHOEF,4 AND A. W. DEKKER' 1 Department of Haematology, Department of Internal Medicine and Medical Oncology, 2 and Department of Clinical J. J.
DE
Microbiology,4 University Hospital Utrecht, and U-Gene Research BV,3 3508 GA Utrecht, The Netherlands Received 21 August 1991/Accepted 29 January 1992
A prospective randomized study was conducted to determine the efficacy of imipenem-cilastatin (hereafter referred to as imipenem) (500 mg four times daily) versus combination therapy for febrile neutropenic patients receiving either no prophylaxis or ciprofloxacin for prevention of infections. Combination therapy consisted of gentamicin (80 mg every 8 h) plus either cefuroxime (1,500 mg every 8 h) or cephalothin (1,000 mg every 4 h) for suspected catheter-related infections. Ninety-four neutropenic fever episodes in 87 patients were evaluable for efficacy. The overall clinical rate of response to imipenem was significantly higher than that to combination therapy (91 versus 74%; P = 0.05). The difference in efficacy was most pronounced in patients with microbiologically documented infections (89 versus 53%; P = 0.025), which were predominantly caused by gram-positive bacteria. Differences in susceptibility may have caused the better rate of response to imipenem. Two of 29 gram-positive bacteria were imipenem resistant, whereas 10 were resistant to cephalothin and cefuroxime and 12 were resistant to gentamicin. No causative gram-negative bacterium and 24 gram-positive bacteria were isolated in 61 fever episodes with ciprofloxacin prophylaxis (oral). In contrast, nine causative gram-negative and five gram-positive bacteria were isolated in 33 episodes without prophylaxis. The difference in distribution proved to be statistically significant for gram-negative (P = 0.0001) as well as gram-positive (P = 0.025) bacteria, indicating that ciprofloxacin effectively prevented the occurrence of gram-negative bacteria and may have contributed to the relatively large number of gram-positive bacteria isolated. Empirical initial therapy with imipenem may be a valuable alternative to combination therapy for neutropenic fever episodes.
Empirical administration of broad-spectrum antibiotics to febrile neutropenic patients has reduced morbidity and mortality from infections (26, 29). The combination of an aminoglycoside plus an antipseudomonal 3-lactam antibiotic has been used extensively (11). Advantages of combination antimicrobial therapy are potential synergistic effects against some gram-negative bacilli (16) and minimal emergence of resistant strains during treatment. Major disadvantages are lack of activity against some gram-positive bacteria and the nephrotoxicity, ototoxicity, and hypokalemia associated with aminoglycosides (19). With the development of broadspectrum antibiotics, individual antibiotic agents may also provide adequate coverage. New agents, such as ceftazidime and imipenem, have been shown to be effective in initial single-agent therapy for febrile neutropenic patients (1, 17, 21, 24, 27). Antibiotic prophylaxis for the prevention of infection is indicated for patients who are expected to be profoundly neutropenic (200 ,umol/liter); history of systemic antimicrobial therapy (other than antibiotics used for prophylaxis) within 72 h of the proposed initiation of the study; intra-abdominal infections, brain abscess, or meningitis; and allogeneic bone marrow transplantation.
Corresponding author. 801
802
ANTIMICROB. AGENTS CHEMOTHER.
CORNELISSEN ET AL.
Treatment. After undergoing an initial evaluation and providing informed consent, patients were randomized to receive either imipenem (500 mg intravenously in 30-min infusions four times daily) or combination therapy. Patients assigned to receive combination therapy received gentamicin at an initial dose of 1.5 mg per kg of body weight and then received 80 mg every 8 h plus either cefuroxime (1,500 mg every 8 h) or cephalothin (1,000 mg every 4 h) for suspected catheter-related infections. Serum aminoglycoside concentrations were checked three times weekly. Doses were adjusted when trough levels exceeded 2 mg/liter or when peak levels did not reach 5 to 10 mg/liter. Special attention was paid to adequate peak levels in patients with gramnegative infections. Clinical and bacteriological evaluation. The initial assessment included history, physical examination, urinalysis, complete blood counts, blood biochemistry, and chest X ray. Specimens for cultures were collected from the throat, urine, feces, and sputum (when available), and at least two blood specimens for blood cultures were taken. Patients were assessed daily for changes in symptoms and signs of infection. Complete blood counts were determined daily, and blood biochemistry was analyzed at least twice a week. Additional X rays were taken when required. Cultures for specimens from any documented site of infection and blood cultures were repeated when patients remained febrile. Bacteriological and fungal culturing of nose, throat, and fecal specimens was performed twice weekly. Organisms isolated from cultures were identified by routine microbiological methods. The antimicrobial susceptibilities of isolated bacteria were determined by agar diffusion on the recommended media (22) with Neo-sensitabs (Rosco, Taastrup, Denmark). For isolates from blood cultures and from patients who did not respond, the MICs of the study drugs were determined by agar dilution in accordance with recommended methods (23) and as previously described (32). Resistance was defined as an MIC of 8 ,tg/ml or more for gentamicin, 16 Fg/ml or more for imipenem, and 32 ,ug/ml or more for cefuroxime and cephalothin. Definition of infection. Fever episodes accompanied by definite clinical signs, indicating a focus of infection, but without specific microbiological proof were termed clinically documented infections. Episodes accompanied by clinical signs with microbiological confirmation were termed bacteriologically documented infections. All other febrile episodes were classified as fever of unknown origin (FUO). Evaluation of response. Patients were assessed at 72 h (and daily thereafter) for response to initial therapy. Response was defined as improvement or resolution of signs and symptoms of infection, with no need for other antibiotics (12). Failure was defined as minimal or no response, necessitating the addition of other antibiotics or modification of the initial regimen to eradicate the primary infection (12). Study drugs were continued for at least 7 days for patients who responded to initial therapy. Vancomycin (500 mg every 6 h) was added to initial therapy with imipenem in the case of failure. Cefuroxime was replaced by either clindamycin (600 mg every 6 h) (in the case of oral mucositis) or piperacillin (4 g every 8 h) (in the case of abdominal mucositis) and gentamicin was continued in patients who had severe mucositis and who showed no response to initial combination therapy. In patients with mild infections associated with the presence of a central venous catheter, combination therapy was replaced by vancomycin monotherapy when methicillinresistant Staphylococcus epidermidis was isolated; in addition, the catheter was removed. In other catheter-related
TABLE 1. Patient characteristics Value for the following group: Gentamicin-
Parameter
No. of patients No. of neutropenic episodes Mean age (range) (yr) No. of females/males No. of patients with the following underlying disease: Acute myeloid leukemia Acute lymphoid leukemia
Lymphoma Carcinoma
Other
Mean no. of days of neutropenia (
Vol. 36, No. 4
Imipenem versus Gentamicin Combined with Either Cefuroxime or Cephalothin as Initial Therapy for Febrile Neutropenic Patients CORNELISSEN,l1* A.
GRAEFF,2 L. F. VERDONCK,1 T. BRANGER,3 M. ROZENBERG-ARSKA,4 J. VERHOEF,4 AND A. W. DEKKER' 1 Department of Haematology, Department of Internal Medicine and Medical Oncology, 2 and Department of Clinical J. J.
DE
Microbiology,4 University Hospital Utrecht, and U-Gene Research BV,3 3508 GA Utrecht, The Netherlands Received 21 August 1991/Accepted 29 January 1992
A prospective randomized study was conducted to determine the efficacy of imipenem-cilastatin (hereafter referred to as imipenem) (500 mg four times daily) versus combination therapy for febrile neutropenic patients receiving either no prophylaxis or ciprofloxacin for prevention of infections. Combination therapy consisted of gentamicin (80 mg every 8 h) plus either cefuroxime (1,500 mg every 8 h) or cephalothin (1,000 mg every 4 h) for suspected catheter-related infections. Ninety-four neutropenic fever episodes in 87 patients were evaluable for efficacy. The overall clinical rate of response to imipenem was significantly higher than that to combination therapy (91 versus 74%; P = 0.05). The difference in efficacy was most pronounced in patients with microbiologically documented infections (89 versus 53%; P = 0.025), which were predominantly caused by gram-positive bacteria. Differences in susceptibility may have caused the better rate of response to imipenem. Two of 29 gram-positive bacteria were imipenem resistant, whereas 10 were resistant to cephalothin and cefuroxime and 12 were resistant to gentamicin. No causative gram-negative bacterium and 24 gram-positive bacteria were isolated in 61 fever episodes with ciprofloxacin prophylaxis (oral). In contrast, nine causative gram-negative and five gram-positive bacteria were isolated in 33 episodes without prophylaxis. The difference in distribution proved to be statistically significant for gram-negative (P = 0.0001) as well as gram-positive (P = 0.025) bacteria, indicating that ciprofloxacin effectively prevented the occurrence of gram-negative bacteria and may have contributed to the relatively large number of gram-positive bacteria isolated. Empirical initial therapy with imipenem may be a valuable alternative to combination therapy for neutropenic fever episodes.
Empirical administration of broad-spectrum antibiotics to febrile neutropenic patients has reduced morbidity and mortality from infections (26, 29). The combination of an aminoglycoside plus an antipseudomonal 3-lactam antibiotic has been used extensively (11). Advantages of combination antimicrobial therapy are potential synergistic effects against some gram-negative bacilli (16) and minimal emergence of resistant strains during treatment. Major disadvantages are lack of activity against some gram-positive bacteria and the nephrotoxicity, ototoxicity, and hypokalemia associated with aminoglycosides (19). With the development of broadspectrum antibiotics, individual antibiotic agents may also provide adequate coverage. New agents, such as ceftazidime and imipenem, have been shown to be effective in initial single-agent therapy for febrile neutropenic patients (1, 17, 21, 24, 27). Antibiotic prophylaxis for the prevention of infection is indicated for patients who are expected to be profoundly neutropenic (200 ,umol/liter); history of systemic antimicrobial therapy (other than antibiotics used for prophylaxis) within 72 h of the proposed initiation of the study; intra-abdominal infections, brain abscess, or meningitis; and allogeneic bone marrow transplantation.
Corresponding author. 801
802
ANTIMICROB. AGENTS CHEMOTHER.
CORNELISSEN ET AL.
Treatment. After undergoing an initial evaluation and providing informed consent, patients were randomized to receive either imipenem (500 mg intravenously in 30-min infusions four times daily) or combination therapy. Patients assigned to receive combination therapy received gentamicin at an initial dose of 1.5 mg per kg of body weight and then received 80 mg every 8 h plus either cefuroxime (1,500 mg every 8 h) or cephalothin (1,000 mg every 4 h) for suspected catheter-related infections. Serum aminoglycoside concentrations were checked three times weekly. Doses were adjusted when trough levels exceeded 2 mg/liter or when peak levels did not reach 5 to 10 mg/liter. Special attention was paid to adequate peak levels in patients with gramnegative infections. Clinical and bacteriological evaluation. The initial assessment included history, physical examination, urinalysis, complete blood counts, blood biochemistry, and chest X ray. Specimens for cultures were collected from the throat, urine, feces, and sputum (when available), and at least two blood specimens for blood cultures were taken. Patients were assessed daily for changes in symptoms and signs of infection. Complete blood counts were determined daily, and blood biochemistry was analyzed at least twice a week. Additional X rays were taken when required. Cultures for specimens from any documented site of infection and blood cultures were repeated when patients remained febrile. Bacteriological and fungal culturing of nose, throat, and fecal specimens was performed twice weekly. Organisms isolated from cultures were identified by routine microbiological methods. The antimicrobial susceptibilities of isolated bacteria were determined by agar diffusion on the recommended media (22) with Neo-sensitabs (Rosco, Taastrup, Denmark). For isolates from blood cultures and from patients who did not respond, the MICs of the study drugs were determined by agar dilution in accordance with recommended methods (23) and as previously described (32). Resistance was defined as an MIC of 8 ,tg/ml or more for gentamicin, 16 Fg/ml or more for imipenem, and 32 ,ug/ml or more for cefuroxime and cephalothin. Definition of infection. Fever episodes accompanied by definite clinical signs, indicating a focus of infection, but without specific microbiological proof were termed clinically documented infections. Episodes accompanied by clinical signs with microbiological confirmation were termed bacteriologically documented infections. All other febrile episodes were classified as fever of unknown origin (FUO). Evaluation of response. Patients were assessed at 72 h (and daily thereafter) for response to initial therapy. Response was defined as improvement or resolution of signs and symptoms of infection, with no need for other antibiotics (12). Failure was defined as minimal or no response, necessitating the addition of other antibiotics or modification of the initial regimen to eradicate the primary infection (12). Study drugs were continued for at least 7 days for patients who responded to initial therapy. Vancomycin (500 mg every 6 h) was added to initial therapy with imipenem in the case of failure. Cefuroxime was replaced by either clindamycin (600 mg every 6 h) (in the case of oral mucositis) or piperacillin (4 g every 8 h) (in the case of abdominal mucositis) and gentamicin was continued in patients who had severe mucositis and who showed no response to initial combination therapy. In patients with mild infections associated with the presence of a central venous catheter, combination therapy was replaced by vancomycin monotherapy when methicillinresistant Staphylococcus epidermidis was isolated; in addition, the catheter was removed. In other catheter-related
TABLE 1. Patient characteristics Value for the following group: Gentamicin-
Parameter
No. of patients No. of neutropenic episodes Mean age (range) (yr) No. of females/males No. of patients with the following underlying disease: Acute myeloid leukemia Acute lymphoid leukemia
Lymphoma Carcinoma
Other
Mean no. of days of neutropenia (
