Ceftizoxime in the treatment of infections in patients with cancer

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1 Journal of Antimicrobial Chemotherapy (98), Suppl. C, Ceftizoxime in the treatment of infections in patients with cancer V. Fainstein, R. Bolivar,. Elting, M. Valdivieso and G. P. Bodey Department of Developmental Therapeutics, Section of Infectious Diseases, The University of Texas, M.D. Anderson Hospital and Tumor Institute at Houston, 673 Bertner Avenue, Houston, Texas 773, U.S.A. One hundred and twenty-three episodes of infections in cancer patients with adequate neutrophil counts were treated with ceftizoxime (low dose: g iv every h, and high dose: g iv every h) for a minimum of 7 days or until days after the patient became afebrile. One hundred and fourteen episodes in patients were evaluated. The overall response rate in 68 patients with documented infection treated with low dose ceftizoxime was % whether or not an organism could be obtained. Twenty of patients (8%) with fever of unknown origin (FUO) also responded to low dose ceftizoxime. The overall response rate in 8 episodes of infection treated with high dose ceftizoxime was 6% in proven infections, 9% when no organism could be found. Six of seven patients with FUO (86%) responded. Overall response rate in Gram-positive infections was 7%; in Gram-negative infections was 7%. Rate of superinfection was low (6%). rate in one-organism infections was 73%; in polymicrobial infections was %. Introduction Infection continues to be a frequent complication in cancer patients despite improvements in antibiotic therapy. Although most infections occur when patients develop neutropenia, serious infections also occur in patients with adequate neutrophil counts who have no overt deficiencies in host defence mechanisms. Often these infections are associated with local factors such as obstruction to natural drainage by tumour, insertion of catheters, or tumour necrosis. These infections may not respond to antibiotic therapy unless the predisposing condition can be corrected. Infections in cancer patients may be caused by a wide variety of aetiological agents. In a review of the causes of death in patients with solid tumours, most fatal infections were caused by aerobic Gram-negative bacilli, especially Escherichia coli and Klebsiella spp. (Inagaki, Rodriguez & Bodey, 97). However, various other organisms were also identified including Gram-positive cocci and anaerobes. Ceftizoxime is a new cephalosporin antibiotic that has excellent in-vitro activity against Gram-positive and Gram-negative bacteria as well as against anaerobes Supported part by a Grant-in-Aid from Fujisiwa SmithKline, Philadelphia, PA and by Grant CA83I from the National Cancer Institute, National Institutes of Health, U.S. Public Health Service, Bethesda, MD Reprint requests to: Victor Fainstein, M.D., M.D. Anderson Hospital, Houston, Texas 773, U.S.A. 3-73/8/C67+ 7 $./ The British Society for Antimicrobial Chemotherapy Downloaded from at Pennsylvania State University on September 8, 6

2 68 V. Fainstein et al. including Bacteroides spp. (Kojo et al., 979; Greenwood et al., 98; Fu & Neu, 98; Bodey, Fainstein & Hinkle, 98). Because of its extended spectrum of activity and because it has few adverse reactions, we have used ceftizoxime as initial therapy for infections in cancer patients with adequate neutrophil counts. Materials and methods This study was conducted on 3 patients with cancer admitted to The University of Texas M.D. Anderson Hospital and Tumor Institute between May 98 and April 98. Patients who were presumed or proven to have an infection were eligible for treatment. Those with acute onset of fever (temperature > F) that persisted more than h were eligible if the fever was not associated with the administration of pyrogenic substances (blood transfusion, immunotherapy) and if the physician's assessment was that infection was the likely cause even if no site could be determined. Patients with chronic fever and no site of infection were ineligible. Most patients had not received any antibiotic. Informed consent was obtained according to institutional policy. Prior to administration of antibiotics, cultures were obtained from blood, urine, throat, and other appropriate sites. Chest X-rays and urinalysis were also obtained. Complete blood cell counts and blood chemistry studies using an automated multiple analysis system were obtained initially and at least twice weekly during therapy. Appropriate follow-up cultures and X-rays were obtained during the course of infection. All patients had neutrophil counts greater than /cu mm. Ceftizoxime was administered intravenously at a dosage of g in ml of % dextrose or normal saline over 3 min (low dose). Doses were repeated at h intervals. When more experience accumulated, the dosage was increased to g iv every h (high dose). Therapy was continued for a minimum of 7 days, or days after the patient became afebrile in patients who responded to therapy. In patients who remained febrile or whose clinical status failed to improve after 3 days, ceftizoxime therapy was considered ineffective, and an aminoglycoside was added or the patient was given another antibiotic regimen, depending on the in-vitro sensitivity of the infecting organism. Patients were judged to have responded if they became afebrile, and if all clinical and laboratory signs of infection disappeared. This included resolution of pulmonary infiltrates on chest X-rays in patients with pneumonia. Those patients who died of their malignant lesion or of other causes were considered to have had a cure if the original infection had resolved, and no evidence of infection was present at postmortem examination. Episodes of fever during which no clinical, radiographic, or bacteriological evidence of infection was found were called fever of unknown origin (FUO). Most organisms causing infection were tested in vitro for susceptibility to ceftizoxime by the serial broth dilution technique (Grove & Randall, 967). Downloaded from at Pennsylvania State University on September 8, 6 Results Of the 3 episodes treated with ceftizoxime, occurring in patients were evaluated for therapeutic response. Nine episodes could not be evaluated due to various protocol violations. There were 6 males and females with a median age of 6 years (range 7-9). The underlying diseases were acute leukaemia in, chronic leukaemia in six, and various solid tumours in 8 patients.

3 Ceftizoxime in the treatment of infections in patients with cancer 69 Sixty-eight patients who had a documented infection were treated with low dose ceftizoxime, and the overall response rate was 9% (Table I). The organism causing infection was identified in patients, and the response rate for these infections was also 9%. In the other 7 patients, an organism could not be obtained, but the response rate was identical. Twenty of (8%) with FUO treated with the low dose also responded. Fourteen patients with documented infection were treated with high dose ceftizoxime, and (79%) responded. In nine of those patients, the organism was identified, and Table I. to ceftizoxime Total Fever of unknown origin Documented infection ow dose ( g-h) Highdose(g-h) Organism identified Organism not identified Episodes % eight patients responded. Infiveof the patients, the organism causing infection could not be cultured, and three patients responded to ceftizoxime. In this group, six of seven patients with FUO (86%) responded. The overall response rate in 8 episodes of infection was 6% (Table I). In bacteriologically proven infections, the overall response rate was 6%. The response rate in cases without an organism was 9%. The most common type of infection was pneumonia (37 episodes), followed by bacteraemia ( episodes), urinary tract infection ( episodes), soft tissue infection ( episodes), cholangitis ( episodes), and each of otitis media, abdominal abscess, lung abscess, and catheter-related infection (Table II). The cure rate with ceftizoxime was significantly higher in patients with bacteraemia (73%) than in patients with pneumonia (37%) (/ > <). Thirteen of 8 (7%) patients with bacteraemia treated with low dose ceftizoxime responded while three of four treated with high dose responded. The organisms causing infection and their response rates are shown in Table III. A single organism caused of these episodes. The other nine episodes (six septicaemias, and one each of cholangitis, soft tissue, and pneumonia were caused by multiple organisms). The most common organisms causing infection were Table II. Efficacy of ceftizoxime by site of infection Downloaded from at Pennsylvania State University on September 8, 6 Site Episodes % Pneumonia Bacteraemia Urinary tract infection Soft tissue Cholangitis Miscellaneous* *One episode each of otitis media, lung abscess, abdominal abscess, and catheter-related infection.

4 7 V. Fainstein et al. Table III. Efficacy of ceftizoxime in infections caused by various organisms Organism Episodes Gram-positive Staph. aureus Staph. epidermidis Group B Streptococcus Enterococcus B. cereus Gram-negative E. coli Klebsiella spp. Acin. calcoaceticus Ser. marcescens Citro. diversus Enterobacter spp. Ps. aeruginosa Pseudomonas spp. Shigella spp. H. influenzae (7%) 6 8(7%) Staphylococcus aureus, E. coli, Klebsiella spp., and Enterococcus. The overall response rate in Gram-positive infections was 7%. All infection due to Staph. aureus responded. The only enterococcal infection that failed to respond was a urinary tract infection (UTI) in which the organism had a minimum inhibitory concentration (MIC) > mg/. The overall response rate in Gram-negative infections was 7%. Only one of three Pseudomonas aeruginosa infections responded. One case of Shigella sp. septicaemia resistant to conventional antibiotics responded satisfactorily. Only three of the nine polymicrobial episodes of infection responded (Table IV). These three episodes were bacteraemias due to Staph. aureus and E. coli; Ps. maltophilia and CDC group 3 B; and Acinetobacter spp., and Staph. epidermidis. Three patients with polymicrobial septicaemia and one with pneumonia expired. The efficacy of ceftizoxime in patients with septicaemia and pneumonia according to the dosage schedule is summarized in Table V. Thirteen of 8 episodes (7%) on low dose and three of four on high dose were cured. Eighteen (9%) of the 37 patients with pneumonia responded to ceftizoxime therapy. Thirty patients failed to produce sputum, Table IV. Efficacy of ceftizoxime in polymicrobial infections Site Organisms Dose* Downloaded from at Pennsylvania State University on September 8, 6 Bacteraemia Staph. aureus+ E. coli Bacteraemia Ps. maltophilia+cdc group 3B Bacteraemia Enterococcus -\-Acinetobacter spp. Bacteraemia Bad. fragilis+ Bacteroides sp. + Streptococcus Bacteraemia Acinetobacter sp. + Staph. epidermidis Soft tissue Proteus sp. + Enterococcus Cholangjtis E. coli+proteus sp.-l- Enterococcus Pneumonia E. coli+proteus sp., ow ( g-h). H, High (g-h). H

5 Ceftizoxime in the treatment of infections in patients with cancer 7 and consequently the infecting organism could not be identified. Seventeen (7%) of these patients responded. Of the seven episodes in which an organism was identified, only one responded (Table V). Nineteen of the 37 (%) episodes of pneumonia occurred in patients with carcinoma of the lung, and ten responded. Thirteen of episodes of UTI responded to ceftizoxime. All infections that responded were due to Gram-negative bacilli. The two failures were due to a resistant enterococcus (MIC > mg/) and a sensitive E. coli (MIC mg/). One patient with Staph. aureus cellulitis responded while another with Proteus spp., failed to respond. The response of the infecting organisms was not completely related to their in-vitro susceptibility to ceftizoxime (Table VI). Nine of infections caused by organisms with Septicaemia Bacteraemia ow dose ( g- h) High dose ( g- h) Pneumonia ow dose ( g-h) High dose ( g- h) Pneumonia identified Organisms Staph. aureus Ps. aeruginosa E. coli Klebsiella spp. Group B Streptococcus Polymicrobial Unidentified organisms MIC (mg/) ow dose group < > High dose group < > Table V. Efficacy of ceftizoxime in bacteraemia and pneumonia Episodes No. of response Table VI. Efficacy of ceftizoxime related to in-vitro susceptibility Organism No. responding % Downloaded from at Pennsylvania State University on September 8, 6 Nine organisms were not available for testing.

6 7 V. Fainstein et al. an MIC of < -78 mg/ responded. Two infections caused by organisms with an MIC > mg/ responded also. Among the patients treated with high dose ceftizoxime, the only failure occurred in an infection caused by an organism with an MIC of > mg/. Only minor side effects were observed during therapy. Five patients developed phlebitis, one had a skin rash, and another developed a drug-induced fever. All of these seven patients were receiving low dose ceftizoxime. No renal, liver, or coagulation abnormalities were attributable to ceftizoxime. Seven patients (6%) acquired superinfections. Six occurred in patients on low dose therapy and were due to fungal infection in three, and E. coli in one. In two cases, the responsible organism could not be identified. In one infection caused by a Pseudomonas sp., the organism developed resistance during therapy. One patient with septicaemia caused by E. coli relapsed when ceftizoxime was discontinued. - Discussion Ceftizoxime is a new /Mactam antibiotic with activity against Gram-positive cocci, Gram-negative bacilli, and most anaerobes including Bacteroides fragilis (Ryan, Kwasnik & Tilton, 98). Since these are the most common organisms causing infections in patients with solid tumours, a clinical evaluation of this compound was undertaken (Inagaki, Rodriguez & Bodey, 97). Ceftizoxime was effective in 6% of 8 episodes of documented infection in cancer patients with normal neutrophil counts. These results compare favourably with previous studies employing single agent therapy. In patients with bacteraemia, ceftizoxime proved to be an effective agent. The response rate was 73% in infections due to a single organism. The response rate in polymicrobial infections was %. In contrast, the overall patient response rate for treating episodes of pneumonia was 9%. Fifty-one per cent of these cases occurred in patients with carcinoma of the lung, most of whom had chronic bronchitis and chronic obstructive pulmonary disease, and they rapidly developed respiratory failure. The aetiological agent was often not identified because the patient was unable to expectorate sputum. This was especially true if the infection was located distal to an obstructive tumour. The therapy of Gram-negative bacillary pneumonia in cancer patients with a single agent is not optimal (Bodey, Valdivieso & Martin, 98). Often in patients with severe underlying conditions, these infections terminate fatally despite proper therapy (Bodey et al., 98ft). The increased incidence of Gram-positive infections in cancer patients is now well recognized, and therefore, therapeutic strategies should include coverage for these organisms. Seventy-five per cent of these infections responded to ceftizoxime in this study. Ceftizoxime is highly stable to penicillinase and cephalosporinase type /?- lactamases (Greenwood el al., 98; Kojo et al., 979). This characteristic and its invitro activity against these organisms make it a valuable agent. The 7% response rate of ceftizoxime against Gram-negative bacillary infections is in accordance with previous in-vitro studies where it has been shown to be extremely effective. However, its activity against Pseudomonas spp. is minimal. Only one of three infections caused by Ps. aeruginosa responded. Since this organism is a common pathogen in cancer patients especially among neutropenic patients (Chang et al., 976), this drug should not be used alone in the therapy of these patients. In-vitro studies have shown antagonism (three of 3 isolates) between ceftizoxime and carbenicillin, and low Downloaded from at Pennsylvania State University on September 8, 6

7 Ceftizoxime in the treatment of infections in patients with cancer 73 grade synergy between ceftizoxime and an aminoglycoside (Fu & Neu, 98). The clinical relevance of these observations remains to be determined. Since most of the patients with normal neutrophil counts have solid tumours (8% in this study), and these tumours usually produce local obstruction, adequate penetration of the antibiotic to the infected site is essential. Hence, we have treated patients with a high dose of ceftizoxime without any added toxicity. Of interest is the fact that 89% of the patients whose infecting organism was identified responded to the high dose therapy, whereas only 9% responded to the low dose (i J <). In this study the occurrence of superinfection was low. This is in contrast with recent reports of colonization and superinfection by resistant organisms in patients with similar compounds (Yu, 98). Ceftizoxime is an effective antibiotic for the therapy of infections in cancer patients. Its greater in-vivo stability and the lack of nephrotoxicity make it a useful therapeutic agent. Although it has a broad antibacterial spectrum of in-vitro activity, its efficacy is limited against Ps. aeruginosa. References Bodey, G. P., Fainstein, V. & Hinkle, A. M. (98a). Comparative in-vitro study of new cephalosporins. Antimicrobial Agents and Chemotherapy, 6-3. Body, G. P., Valdivieso, M. & Martin,. (986). Cefoxitin therapy of infections in cancer patients. Current Therapeutic Research 9, 9-3. Chang, H. Y., Rodriguez, V., Narboni, G. & Bodey, G. P. (976). Causes of death in adults with acute leukopenia. Medicine, Fu, K. & Neu, H. C. (98). Antibacterial activity of ceftizoxime, a /7-lactamase stable cephalosporin. Antimicrobial Agents and Chemotherapy 7, Greenwood, D., Pearson, N., Eley, A. & O'Grady, F. (98). Comparative in-vitro activities of cefotaxime and ceftizoxime (FK79): new cephalosporins with exceptional potency. Antimicrobial Agents and Chemotherapy 7, Grove, D. A. & Randall, W. A. (967). Assay methods of antibiotics. aboratory Manual, pp , Medical Encyclopedia Inc., New York. Inagaki, J., Rodriguez, V. & Bodey, G. P. (97). Causes of death in cancer patients. Cancer 33, Kojo, H., Nishida, M., Goto, S. & Kuwahara, S. (979). Antibacterial activity of ceftizoxime (FK 79), a new cephalosporin, against cephalosporin-resistant bacteria, and its stability to /?- lactamase. Antimicrobial Agents and Chemotherapy 6, 9-3. Ryan, R. W., Kwasnik, I. & Tilton, R. C. (98). The activity of five cephalosporins against Bacteroides fragilis. Annals of Clinical and aboratory Science, 3-. Yu, V.. (98). Enterococcal superinfection and colonization after therapy with moxalactam, a broad-spectrum antibiotic. Annals of Internal Medicine 9, 78-. Downloaded from at Pennsylvania State University on September 8, 6